Sustained release matrix systems for highly soluble drugs

ABSTRACT

Disclosed are sustained release oral solid dosage forms comprising a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l; a pH modifying agent; and a sustained release matrix comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing a sustained release of said medicament after oral administration to human patients.

This application claims the benefit of provisional application Ser. No.60/157,200 filed Sep. 30, 1999, the disclosure of which is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The advantages of controlled release products are well known in thepharmaceutical field and include the ability to maintain a desired bloodlevel of a medicament over a comparatively longer period of time whileincreasing patient compliance by reducing the number of administrationsnecessary to achieve the same. These advantages have been attained by awide variety of methods. For example, different hydrogels have beendescribed for use in controlled release medicines, some of which aresynthetic, but most of which are semi-synthetic or of natural origin. Afew contain both synthetic and non-synthetic material. However, some ofthe systems require special process and production equipment, and inaddition some of these systems are susceptible to variable drug release.

Oral controlled release delivery systems should ideally be adaptable sothat release rates and profiles can be matched to physiological andchronotherapeutic requirements.

For the most part, the release rate of oral delivery systems have beenclassified according to the mechanism of release, such as zero order,first order, second order, pseudo-first order, and the like, althoughmany pharmaceutical compounds release medicament via other, complicatedmechanisms.

First order mechanisms refer to situations where the reaction rate isdependent on the concentration of the reacting substance (and thereforeis dependent on the first power of the reactant). In such mechanisms,the substance decomposes directly into one or more products.

Second order mechanisms occur when the experimentally determined rate ofreaction is proportional to the concentration of each of two reactants,or to the second power of the concentration of one reactant.

Pseudo first order reactions are generally defined as second orderreactions which behave as though they are governed by a first ordermechanism, and occur, for example, when the amount of one reactingmaterial is manipulated by being present in great excess or beingmaintained at a constant concentration as compared to the othersubstance. In such circumstances, the reaction rate is determined by themanipulated substance.

Zero order mechanisms refer to situations where the reaction rate isindependent of the concentration of the reacting substance (andtherefore is dependent on the zero power of the reactant), the limitingfactor being something other than the concentration of the reactingsubstance (e.g., the medicament). The limiting factor in a zero ordermechanism may be, for example, the solubility of the reacting substanceor the light intensity in photochemical reactions.

As previously mentioned, however, many chemical reactions are not simplereactions of zero-, first-, or second-order, and the like, and insteadcomprise a combination of two or more reactions.

Moreover, other factors may influence the reaction rate, includingtemperature, pH, food effect variability, ions and ionic strengthdependency, viscosity dependency, corrosion/erosion variability, contentuniformity problems, flow and weight uniformity problems, carryingcapacity and mechanical strength problems, hydrolysis, photochemicaldecomposition, interaction between components (such as interactionsbetween the drug and other ingredients in the formulation, such asbuffers, preservatives, and the like), the concentration of solvents oflow dielectric constant (when the reaction involves oppositely chargedions), etc.

While many controlled and sustained release formulations are alreadyknown, certain soluble to highly soluble drugs present formulationdifficulties when included in such formulations. Sustained releaseformulations with soluble drugs are susceptible to “dose dumping”. Thisoccurrence is where the release of the active ingredient is delayed, butwhen release is initiated, the rate is extremely high. This elevatedrelease rate is associated with blood plasma fluctuations which canpossibly result in decreased therapeutic effect or increased toxicity.These are the same problems which sustained release formulations aresupposed to solve.

Further, it is often not possible to readily predict whether aparticular sustained release formulation will provide the desiredsustained release for a soluble to highly soluble drug. It has generallybeen found that it is necessary to carry out considerableexperimentation to obtain sustained release formulations providing thedesired bio availability of such drugs when ingested.

In order to compensate for the unpredictability associated with having acontrolled release formulation provide the desired sustained release fora soluble to highly soluble drug, it is sometimes considered desirableto provide a formulation with bi-modal or multi-phasic kinetics. Bimodalor multi-phasic release may be characterized by an initial high ratefollowed by a slower rate as the dosage form passes the upper portion ofthe small intestine where absorption is maximum and finally anotherhigher rate as the dosage form passes into the further end of theintestine where absorption is less than before.

Bimodal release is considered to be advantageous for a number ofreasons, including but not limited to the fact that bimodal releaseallows the formulator to compensate for changing absorption rates of themedicament in the gastrointestinal tract by providing a rapid onset, ofaction (when the formulation is located in the stomach) and compensatefor relatively slow absorption by providing a relatively rapid releaserate (e.g., when the formulation is located in the large intestine).

Bimodal release formulations have been provided in a number of differentmanners to date.

For example, International Publication Number WO/87/00044 describestherapeutic formulations which are said to have bimodal releasecharacteristics. WO 87/00044 describes a carrier base material fortherapeutically active medicaments in a solid dosage formulation thatare said to produce a bimodal controlled release profile characterizedby a rapid initial release of medicament followed by a substantiallyconstant rate of release for a period of time, after which the releaserate is greater than the constant rate previously observed. The carrierbased material comprises bimodal hydroxypropylmethylcellulose etherswith a methoxy content of 19-30%, a hydroxy propoxy content of 4-12%, aviscosity of 40-19,000 cps, an average molecular weight of20,000-140,000, and which demonstrates a bimodal release profile inaccordance with an assay method described therein. The bimodalhydroxypropylmethylcelluloses comprise 5-99% by weight of the totalformulation, depending upon the active ingredient and length of drugreleased desire.

A. C. Shah et al., “Gel-Matrix Systems Exhibiting Bimodal ControlledRelease For Oral Drug Delivery”, Journal of Controlled Release, 9(1989), pp. 169-175, further reported that certain “types” ofhydroxypropylmethylcellulose ethers are found to display a bimodal drugrelease profile. However, in that study, series ofhydroxypropylmethylcellulose ether polymers were found to providebimodal and non-bimodal release profiles from polymer-drug matrixtablets, which results appeared to depend upon the supplier of thepolymer (and therefore upon, e.g., the method of manufacture, ioniccomposition, variations in the distribution of substituent groups, ordistribution of molecular weight fractions).

P. Giunchedi et al., “Ketoprofen Pulsatile Absorption From ‘MultipleUnit’ Hydrophilic Matrices” International Journal of Pharmaceutics, 77(1991), pp. 177-181 described an extended release oral formulation ofKetoprofen comprising a multiple unit formulation constituted by fourhydrophilic matrices of identical composition, each containing 50 mg ofdrug and prepared with hydroxypropylmethylcellulose (Methocel®) andplaced in a gelatin capsule. Pulsatile plasma levels (2 peaks at 2nd and8th hours after dosing) were said to be obtained, whereas in vitro testsresulted in a fairly constant drug release.

U. Conte et al., “A New Ibuprofen Pulsed Release Oral Dosage Form”, DrugDevelopment And Industrial Pharmacy, 15(14-16), pp 2583-2596 (1989)reported that a pulsed released pattern was obtained from a 3-layertablet wherein two layers contained a dose of drug, and an intermediatelayer acted as a control element separating the drug layers. The controlelement was a mixture of water-swellable polymers(hydroxypropylmethylcelluloses). An outer film of an impermeable polymercoated the tablet. A superdisintegrant (sodium starch glycolate andcross-linked polyvinyl pyrrolidone) was included in the drug layers.

K. A. Kahn et al, “Pharmaceutical Aspects And In-Vivo Performance OfBrufen Retard—An Ibuprofen SR Matrix Tablet”, Proced. Intern. Symp.Control. Rel. Bioact. Mater., 18 (1991), Controlled Release Society,Inc., describes a formulation containing 800 mg of ibuprofen which issaid to provide a bimodal release pattern. The release retarding agentutilized therein was xanthan gum. The ingredients were blended to theappropriate xanthan gum content, and thereafter compressed into tabletsand film coated. The amount of xanthan gum included inversely affectedthe rate of drug release. An increase in drug particle size or quantityof film-coat per tablet did not significantly effect the rate of drugrelease. Although an increase in particle size of the xanthan gum causeda more pronounced burst effect, the application of the film-coatovercame this burst effect. The rapid initial release of the medicamentwas hypothesized to be related to changes in the formation of the gellayer, wherein larger particles gel more slowly and are sloughed offbefore a coherent matrix can form.

In our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, herebyincorporated by reference, we reported that a controlled releaseexcipient which is comprised of synergistic heterodispersepolysaccharides (e.g., a heteropolysaccharide such as xanthan gum incombination with a polysaccharide gum capable of cross-linking with theheteropolysaccharide, such as locust bean gum) is capable of processinginto oral solid dosage forms using either direct compression, followingaddition of drug and lubricant powder, conventional wet granulation, ora combination of the two. The release of the medicament from theformulations therein proceeded according to zero-order or first-ordermechanisms.

Our own U.S. Pat. Nos. 5,472,711 and 5,478,574, hereby incorporated byreference, we report a formulation capable of providing multi-phasic orbi-phasic controlled release of a therapeutically active medicament invitro by incorporating an effective amount of a pharmaceuticallyacceptable surfactant with the above-referenced excipient.

An example of a highly soluble drug used in the present invention isdiltiazem, which is a benzothiazine derivative possessing calciumantagonist activity. Diltiazem is widely used in the treatment ofhypertension and angina. Accordingly, a great deal of attention has beengiven to the preparation of sustained release diltiazem which providesan acceptable release profile. For example U.S. Pat. Nos. 4,894,240 and5,364,620 (Geoghegan, et al.) describe a diltiazem pellet formulationsuitable for once daily administration. This formulation comprises adiltiazem core in association with an organic acid, surrounded by aninsoluble multi-layer membrane. The membrane allows the release ofdiltiazem from the pellet at a rate allowing controlled absorption overa 24 hour period following administration.

Other techniques have been described in the prior art for preparingsustained release diltiazem formulations. For example, U.S. Pat. No.5,419,917 (Chen et al.) describes a composition which controls the rateof release of diltiazem from a hydrogel using a pharmaceuticallyeffective ionizable compound.

Another example of a highly soluble drug used in the present inventionis oxybutynin. Oxybutynin is widely used in the treatment of urologicaldisorders, e.g., hyperactive bladder. Our own U.S. Pat. No. 5,399,359discloses an oxybutynin sustained release formulation comprising apharmaceutically effective amount of oxybutynin dispersed within asustained release matrix comprising a gelling agent, an effective amountof a pharmaceutically acceptable water-soluble cationic cross-linkingagent which cross-links with the gelling agent when the formulation isexposed to an environmental fluid, e.g., gastrointestinal fluid, and aninert diluent.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a bioavailablesustained release formulation for soluble to highly solubletherapeutically active medicaments.

It is a further object of the present invention to provide a formulationwhich can provide multi-phasic or bi-phasic controlled release forsoluble to highly soluble medicaments.

It is a further object of the present invention to provide a method forpreparing a bioavailable sustained release formulation for soluble tohighly soluble therapeutically active medicaments.

It is yet another object of the present invention to provide a sustainedrelease matrix which may be used in the preparation of a sustainedrelease oral solid dosage, form of soluble to highly solubletherapeutically active medicaments.

It is a further object of the present invention to provide a sustainedrelease matrix which is suitable for providing, when combined with amedicament, a sustained release formulation which providestherapeutically effective blood levels of the medicament for e.g., 12 or24 hours.

It is a further object of the invention to provide a diltiazem sustainedrelease matrix formulation which provides a plasma profile similar tocommercially available sustained release formulations, e.g., CardizemCD.

It is a further object of the invention to provide a oxybutyninsustained release matrix formulation which provides a plasma profilesimilar to commercially available sustained release formulations, e.g.,Ditropan XL.

The above-mentioned objects and others are achieved by virtue of thepresent invention, which relates in part to the surprising discoverythat the incorporation of a pH modifying agent into a dosage formcomprising a gelling agent, facilitates the release of the drug from thedosage form and provides a high bioavailability.

In certain embodiments, the sustained release oral solid dosage formcomprises a therapeutically effective amount of a medicament having asolubility of more than about 10 g/l; a pH modifying agent; and asustained release matrix comprising a gelling agent, the gelling agentcomprising a heteropolysaccharide gum and a homopolysaccharide gumcapable of cross-linking the heteropolysaccharide gum when exposed to anenvironmental fluid. Preferably, the dosage form provides a sustainedrelease of the medicament for at least about 12 hours, preferably atleast about 24 hours.

In certain embodiments, the dosage form further comprises a) apharmaceutically acceptable surfactant which can provide a multi-phasicrelease of the drug; b) an inert diluent selected from, e.g., amonosaccharide, a disaccharide, a polyhydric alcohol, or mixturesthereof; c) a hydrophobic material to slow the hydration of the gellingagent; and/or d) an effective amount of a pharmaceutically acceptableionizable gel strength enhancing agent suitable for modifying therelease rate from the gel which is formed when the controlled releaseformulation is exposed to an environmental fluid. In a preferredembodiment, the formulation of the present invention comprises a tablet.

In a preferred embodiment of the invention, the ratio of medicament togelling agent is preferably from about 10:1 to about 1:10, morepreferably from about 5:1 to about 1:5, and most preferably from about1.25:1 to about 2:1.

The present invention is also related to a method for providing asustained release formulation of a medicament having high solubility inwater, comprising preparing a matrix comprising a gelling agentcomprising a heteropolysaccharide gum and a homopolysaccharide gumcapable of cross-linking said heteropolysaccharide gum when exposed toan environmental fluid; an optional ionizable gel strength enhancingagent, an optionally inert pharmaceutical diluent; and an optionalhydrophobic material, and thereafter adding a soluble to highly solublemedicament, a pH modifying agent and an optional pharmaceuticallyacceptable surfactant. Thereafter the resulting mixture is tableted suchthat a product is obtained having a ratio of medicament to gelling agentfrom about 10:1 to about 1:10, more preferably from about 5:1 to about1:5, and most preferably from about 1.25:1 to about 2:1, such that a gelmatrix is created when the tablet is exposed to an environmental fluidand such that the tablets each contain a therapeutically effectiveamount of the medicament. The resulting tablet provides therapeuticallyeffective blood levels of the medicament for at least about 12 hours,and preferably about 24 hours.

The present invention is further related to a method of treating apatient by orally administering an oral solid dosage form as set forthabove.

In certain preferred embodiments of the invention, the matrix can beprepared from a pre-granulated sustained release excipient comprising,e.g. from about 10 to about 99% by weight of a gelling agent, from about0 to about 20% by weight of an ionizable gel strength enhancing agent,from about 1 to about 89% by weight of an inert pharmaceutical diluent,and from about 1 to about 20% of a hydrophobic material.

In other preferred embodiments the mixture of the matrix and inertdiluent are granulated before the addition of the medicament, with adispersion or solution of the hydrophobic material in an amountsufficient to slow the hydration of the matrix without disrupting thesame.

In other preferred embodiments of the invention, a first portion of themedicament is introduced during the granulation of the excipient, and asecond portion of the drug is introduced extragranularly, or after thegranulation step. Such an embodiment provides an initial rapid releaseof the medicament.

In preferred embodiments, the medicament is highly soluble, i.e., has asolubility of more than about 100 g/l.

In other preferred embodiment, the medicament comprises a calciumchannel blacker, preferably a benzothiazine, most preferably diltiazemor a pharmaceutically acceptable salt thereof.

In other preferred embodiments, the medicament comprises anantispasmodic, preferably oxybutynin or a pharmaceutically acceptablesalt thereof.

By “sustained release” it is meant for purposes of the present inventionthat the therapeutically active medicament is released from theformulation at a controlled rate such that therapeutically beneficialblood levels (but below toxic levels) of the medicament are maintainedover an extended period of time, e.g., at least about 12 hour or atleast about 24 hours.

By “bioavailable” it is meant for purposes of the present invention thatthe therapeutically active medicament is absorbed from the sustainedrelease formulation and becomes available in the body at the intendedsite of drug action, preferably within 80% of a reference standard(based on comparison of the AUC).

By “soluble”, it is meant that the therapeutically active medicament hasan aqueous solubility of more than about 10 grams per liter (g/l).

By “highly soluble”; it is meant that the therapeutically activemedicament has an aqueous solubility of more than about 100 grams perliter (g/l).

The term “environmental fluid” is meant for purposes of the presentinvention to encompass, e.g., an aqueous solution, or gastrointestinalfluid.

The term “pH modifying agent” is meant for purposes of the presentinvention to mean any substance which decreases the ionization of themedicament, whereby the release of the drug from the hydrogel matrix andinto solution is facilitated.

The term “Cmax” is meant for purposes of the present invention to meanthen maximum plasma concentration of a medicament achieved afteradministration of a dosage form in accordance with the invention.

The term “Tmax” is meant for purposes of the present invention to meanthe elapsed time from administration of a dosage form to the time theCmax of the medicament is achieved

The term “W₅₀” is meant for purposes of the present invention to meanthe time period measured by the width of the plasma concentration curveat 50% of the height of the Cmax.

For purposes of the present invention, the dosage form can have bi-modalkinetics, and accordingly, there can be multiple Cmaxs, Tmaxs and W₅₀sfor the disclosed dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 1 and 2.

FIG. 2 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 3 and 4.

FIG. 3 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 5 and 6.

FIG. 4 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 7 and 8.

FIG. 5 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 9 and 10.

FIG. 6 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 11 and 12.

FIG. 7 is a graphical representation of the % release rate over time forExamples 11 and 12.

FIG. 8 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 13 and 18.

FIG. 9 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 19 and 20.

FIG. 10 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 21-23.

FIG. 11 is a graphical representation of the mean plasma diltiazemconcentration (ng/ml) over time for Example 24 and for a referencestandard (Cardizem CD 240 mg).

FIG. 12 is a graphical representation of the mean plasma diltiazemconcentration (ng/ml) over time for Examples 25 and for a referencestandard (Cardizem CD 240 mg).

FIG. 13 is a graphical representation of the dissolution (mean percentdissolved over time) for Examples 26 and 27.

FIG. 14 is a graphical representation comparing the dissolution (meanpercent dissolved over time) of Example 37 and for a reference standard(Ditropan XL).

DETAILED DESCRIPTION

The sustained release matrix of the present invention can be aheterodisperse excipient (as previously reported in our U.S. Pat. Nos.4,994,276, 5,128,143, and 5,135,757) which can comprise a gelling agentof both hetero- and homo-polysaccharides which exhibit synergism, e.g.,the combination of two or more polysaccharide gums produce a higherviscosity and faster hydration than that which would be expected byeither of the gums alone, the resultant gel being faster-forming andmore rigid.

The term “heteropolysaccharide” as used in the present invention isdefined as a water-soluble polysaccharide containing two or more kindsof sugar units, the heteropolysaccharide having a branched or helicalconfiguration, and having excellent water-wicking properties and immensethickening properties.

An especially preferred heteropolysaccharide is xanthan gum, which is ahigh molecular weight (>10⁶) heteropolysaccharide. Other preferredheteropolysaccharides include derivatives of xanthan gum, such asdeacylated xanthan gum, the carboxymethyl ether, and the propyleneglycol ester.

The homopolysaccharide gums used in the present invention which arecapable of cross-linking with the heteropolysaccharide include thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose. Galactomannans which have higher proportions ofunsubstituted mannose regions have been found to achieve moreinteraction with the heteropolysaccharide. Locust bean gum, which has ahigher ratio of mannose to the galactose, is especially preferred ascompared to other galactomannans such as guar and hydroxypropyl guar.

The controlled release properties of the controlled release formulationsof the present invention may be optimized when the ratio ofheteropolysaccharide gum to homopolysaccharide material is about 1:1.5,although heteropolysaccharide gum in an amount of from about 10 to about90 percent or more by weight of the heterodisperse polysaccharidematerial provides an acceptable slow release product. The combination ofany homopolysaccharide gums known to produce a synergistic effect whenexposed to aqueous solutions may be used in accordance with the presentinvention. It is also possible that the type of synergism which ispresent with regard to the gum combination of the present inventioncould also occur between two homogeneous or two heteropolysaccharides.Other acceptable gelling agents which may be used in the presentinvention include those gelling agents well-known in the art. Examplesinclude vegetable gums such as alginates, carrageenan, pectin, guar gum,modified starch, hydroxypropylmethylcellulose, methylcellulose, andother cellulosic materials such as sodium carboxymethylcellulose andhydroxypropyl cellulose. This list is not meant to be exclusive.

The inert diluent of the sustained release excipient preferablycomprises a pharmaceutically acceptable saccharide, including amonosaccharide, a disaccharide, or a polyhydric alcohol, and/or mixturesof any of the foregoing. Examples of suitable inert pharmaceuticalfillers include sucrose, dextrose, lactose, microcrystalline cellulose,fructose, xylitol, sorbitol, starches, mixtures thereof and the like.However, it is preferred that a soluble pharmaceutical filler such aslactose, dextrose, sucrose, or mixtures thereof be used. The inertdiluent or filler may alternatively comprise a pre-manufactured directcompression diluent as set forth below.

For example, it is possible to dry mix the ingredients of the sustainedrelease excipient without utilizing a wet granulation step. Thisprocedure may be utilized, for example, where a wet granulation is to beaccomplished when the active ingredient is directly added to theingredients of the sustained release excipient. On the other hand, thisprocedure may also be used where no wet granulation step whatsoever iscontemplated. If the mixture is to be manufactured without a wetgranulation step, and the final mixture is to be tableted, it ispreferred that all or part of the inert diluent comprise apre-manufactured direct compression diluent. Such direct compressiondiluents are widely used in the pharmaceutical arts, and may be obtainedfrom a wide variety of commercial sources. Examples of suchpre-manufactured direct compression excipients include Emcocel®(microcrystalline cellulose, N.F.), Emdex® (dextrates, N.F.), andTab-Fine® (a number of direct-compression sugars including sucrose,fructose and dextrose), all of which are commercially available fromPenwest Pharmaceuticals Co., Patterson, N.Y. ). Other direct compressiondiluents include Anhydrous lactose (Lactose N.F., anhydrous directtableting) from Sheffield Chemical, Union, N.J. 07083; Elcems® G-250(powdered cellulose), N.F.) from Degussa, D-600 Frankfurt (Main)Germany; Fast-Flo Lactose® (Lactose, N.F., spray dried) from ForemostWhey Products, Banaboo, Wis. 53913; Maltrin® (Agglomerated maltodextrin)from Grain Processing Corp., Muscatine, Iowa 52761; Neosorb 60®(Sorbitol, N.F., direct-compression from Roquet Corp., 645 5th Ave., NewYork, N.Y. 10022; Nu-Tab® (Compressible sugar, N.F.) from IngredientTechnology, Inc., Pennsauken, N.J. 08110; Polyplasdone XL®(Crospovidone, N.F., cross-linked polyvinylpyrrolidone) from GAF Corp.,New York, N.Y. 10020; Primojel® (Sodium starch glycolate, N.F.,carboxymethyl starch) from Generichem Corp., Little Falls, N.J. 07424;Solka Floc® (Cellulose floc) from Penwest Pharmaceuticals Co.,Patterson, N.Y. 10512; Spray-dried Lactose® (Lactose N.F., spray dried)from Foremost. Whey Products, Baraboo, Wis. 53913 and DMV Corp., Vehgel,Holland; and Sta-Rx 1500® (Starch 1500) (Pregelatinized starch, N.F.,compressible) from Colorcon, Inc., West Point, Pa. 19486.

In general, the formulation may be prepared as a directly compressiblediluent, for example, by wet granulating, spray drying lactose or as apremixed direct compression diluent by art known methods. For purposesof the present invention, these specially treated inert diluents will bereferred to as “directly compressible” inert diluents.

In certain embodiments, the ingredients of the sustained releaseexcipient can be pre-manufactured. However, in other embodiments theactive drug can be added to the excipient ingredients and that mixturemelt granulated to form a granulation. Finally, where a surfactant isused, the surfactant comprising the solubilized or dispersed diltiazemor oxybutynin can be added directly to the mixture of ingredients.

In further embodiments of the present invention, the directlycompressible inert diluent which is used in conjunction with thesustained release pharmaceutical excipient of the present invention isan augmented microcrystalline cellulose as disclosed in U.S. patentapplication Ser. No. 08/370,576, filed Jan. 9, 1995, and entitled“PHARMACEUTICAL EXCIPIENT HAVING IMPROVED COMPRESSIBILITY”, by J.Staniforth, B. Sherwood and E. Hunter, hereby incorporated by referencein its entirety. The augmented microcrystalline cellulose describedtherein is commercially available under the tradename “Prosolv” fromPenwest Pharmaceuticals Co.

An effective amount of a pharmaceutically acceptable surfactant can alsobe added to the above-mentioned ingredients of the excipient, or addedat the time the medicament is added, in order to increase thebioavailability of the medicament. An example of a suitable surfactantis docusate sodium in an amount up to about 15% by weight of the soliddosage form. An especially preferred surfactant is sodium lauryl sulfatein an amount up to about 15% by weight of the solid dosage form.

In one embodiment, the surfactant is dissolved in a suitable solventsuch as water, and is thereafter added to the blended mixture of thesustained release excipient and the medicament. This allows thesurfactant to wet the particles of the excipient such that when thesolvent evaporates the particles of the medicament which precipitate aretiny and do not aggregate. A granulate of the medicament and thesurfactant is obtained which is preferably finely and homogeneouslydispersed in the excipient.

In certain embodiments of the present invention, e.g. wherein themedicament is diltiazem or oxybutynin, the surfactant is included in anamount e.g., from about 0.1% to about 5%, or from about 1% to about 15%of the final product, by weight. However, the upper limit of surfactantincluded can be higher than 15%. One limiting factor is that the finalproduct should provide a pharmaceutically acceptable formulation. Forexample, in the case of tablets, the upper limit of the amount ofsurfactant included is determined by the production of apharmaceutically acceptable tablet, e.g., a tablet which has afriability of less than about 1% and a hardness of 6-8 kg.

The surfactants which may be used in the present invention generallyinclude pharmaceutically acceptable anionic surfactants, cationicsurfactants, amphoteric (amphipathic/amphophilic) surfactants, andnon-ionic surfactants. Suitable pharmaceutically acceptable anionicsurfactants include, for example, monovalent alkyl carboxylates, acyllactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalentalkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates,sulfuric acid esters, alkyl sulfates (including sodium lauryl sulfate(SLS)), ethoxylated alkyl sulfates, ester linked sulfonates (includingdocusate sodium or dioctyl sodium succinate (DSS)), alpha olefinsulfonates, and phosphated ethoxylated alcohols.

Suitable pharmaceutically acceptable cationic surfactants include, forexample, monoalkyl quaternary ammonium salts, dialkyl quaternaryammonium compounds, amidoamines, and aminimides.

Suitable pharmaceutically acceptable amphoteric(amphipathic/amphophilic) surfactants, include, for example,N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkylβ-aminoproprionates.

Other suitable surfactants for use in conjunction with the presentinvention include polyethyleneglycols as esters or ethers. Examplesinclude polyethoxylated castor oil, polyethoxylated hydrogenated castoroil, polyethoxylated fatty acid from castor oil or polyethoxylated fattyacid from castor oil or polyethoxylated fatty acid from hydrogenatedcastor oil. Commercially available surfactants which can be used areknown under trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emerest2675, Lipal 395 and PEG 3350.

The pH modifying agent facilitates the release of the drug from thematrix and is present from about 1% to about 50%; from about 1% to about25% from about 1% to about 15%; or from about 1% to about 10% by weightof the final dosage form. In preferred embodiments, the pH modifyingagent is an organic acid such as citric acid, succinic acid, fumaricacid, malic acid, maleic acid, glutaric acid or lactic acid.

The ionizable gel strength enhancing agent which is optionally used inconjunction with the present invention may be monovalent or multivalentmetal cations. The preferred salts are the inorganic salts, includingvarious alkali metal and/or alkaline earth metal sulfates, chlorides,borates, bromides, citrates, acetates, lactates, etc. Specific examplesof suitable ionizable gel strength enhancing agent include calciumsulfate, sodium chloride, potassium sulfate, sodium carbonate, lithiumchloride, tripotassium phosphate, sodium borate, potassium bromide,potassium fluoride, sodium bicarbonate, calcium chloride, magnesiumchloride, sodium citrate, sodium acetate, calcium lactate, magnesiumsulfate and sodium fluoride. Multivalent metal cations may also beutilized. However, the preferred ionizable gel strength enhancing agentare bivalent. Particularly preferred salts are calcium sulfate andsodium chloride. The ionizable gel strength enhancing agent of thepresent invention are added in an amount effective to obtain a desirableincreased gel strength due to the cross-linking of the gelling agent(e.g., the heteropolysaccharide and homopolysaccharide gums). Inalternate embodiments, the ionizable gel strength enhancing agent isincluded in the sustained release excipient of the present invention inan amount from about 1 to about 20% by weight of the sustained releaseexcipient, and in an amount 0.5% to about 16% by weight of the finaldosage form.

In certain embodiments of the present invention, the sustained releasematrix of the present invention comprises a sustained release excipientwhich comprises from about 10 to about 99 percent by weight of a gellingagent comprising a heteropolysaccharide gum and a homopolysaccharidegum, from about 0 to about 20 percent by weight of an ionizable gelstrength enhancing agent, and from about 1 to about 89 percent by weightof an inert pharmaceutical diluent. In other embodiments, the sustainedrelease excipient comprises from about 10 to about 75 percent gellingagent, from about 2 to about 15 percent ionizable gel strength enhancingagent, and from about 30 to about 75 percent inert diluent. In yet otherembodiments, the sustained release excipient comprises from about 30 toabout 75 percent gelling agent, from about 5 to about 10 percentionizable gel strength enhancing agent, and from about 15 to about 65percent inert diluent.

The sustained release excipient of the present invention (with orwithout the optional ionizable gel strength enhancing agent) may befurther modified by incorporation of a hydrophobic material which slowsthe hydration of the gums without disrupting the hydrophilic matrix.This is accomplished in alternate embodiments of the present inventionby granulating the sustained release excipient with the solution ordispersion of a hydrophobic material prior to the incorporation of themedicament. The hydrophobic polymer may be selected from analkylcellulose such as ethylcellulose, other hydrophobic cellulosicmaterials, polymers or copolymers derived from acrylic or methacrylicacid esters, copolymers of acrylic and methacrylic acid esters, zein,waxes, shellac, hydrogenated vegetable oils, and any otherpharmaceutically acceptable hydrophobic material known to those skilledin the art. The amount of hydrophobic material incorporated into thesustained release excipient is that which is effective to slow thehydration of the gums without disrupting the hydrophilic matrix formedupon exposure to an environmental fluid. In certain preferredembodiments of the present invention, the hydrophobic material isincluded in the sustained release excipient in an amount from about 1 toabout 20 percent by weight. The solvent for the hydrophobic material maybe an aqueous or organic solvent, or mixtures thereof.

In embodiments where the sustained release excipient of the presentinvention has been pre-manufactured, it is then possible to blend thesame with the medicament, e.g., in a high shear mixer. In certainespecially preferred embodiments, the medicament is a therapeuticallyeffective benzothiazine which are useful for the treatment ofcirculatory disorders and high blood pressure. An especially preferreddihydropyridine is diltiazem. Useful formulations of diltiazem generallycontain daily doses from about 30 to about 500 mg, preferably from about120 mg to about 480 mg. In certain preferred embodiments of the presentinvention, the dosage form includes a dosage of diltiazem in an amountof 120 mg, 180 mg, 240 mg, or 300 mg for 24 hour formulations; and adosage of diltiazem in an amount of 60 mg, 90 mg and 120 mg for 12 hourformulations.

In certain other especially preferred embodiments, the medicament isoxybutynin which is useful for the treatment of urological disorders.Useful formulations of oxybutynin generally contain daily doses fromabout 2.5 mg to about 50 mg, e.g., from about 2.5 mg to about 25 mg for12 hour formulations and from about 5 mg to about 50 mg for 24 hourformulations. In certain preferred embodiments of the present invention,the dosage form includes a dosage of oxybutynin in an amount of 5 mg, 10mg, or 15 mg for 24 hour formulations.

An effective amount of any generally accepted pharmaceutical lubricant,including calcium or magnesium soaps is preferably added to the mixtureof ingredients (including medicament) prior to compression of themixture into oral solid dosage forms, such as tablets. An example of asuitable lubricant is magnesium stearate in an amount of about 0.5 toabout 3% by weight of the solid dosage form. An especially preferredlubricant is sodium stearyl fumarate, NF, commercially available underthe trade name Pruv® from Penwest Pharmaceuticals Co.

The sustained release excipients of the present invention have uniformpacking characteristics over a range of different particle sizedistributions and are capable of processing into the final dosage form(e.g., tablets) using either direct compression, following addition ofdrug and lubricant powder, or conventional wet granulation.

The properties and characteristics of a specific excipient systemprepared according to the present invention is dependent in part on theindividual characteristics of the homo and heteropolysaccharideconstituents, in terms of polymer solubility, glass transitiontemperatures etc., as well as on the synergism both between differenthomo- and heteropolysaccharides and between the homo andheteropolysaccharides and the inert saccharide constituent(s) inmodifying dissolution fluid-excipient interactions.

The combination of the gelling agent (i.e., a mixture of xanthan gum andlocust bean gum) with the inert diluent, with or without the ionizablegel strength enhancing agent and hydrophobic polymer, provides aready-to-use sustained release excipient product in which a formulatorneed only blend the desired active medicament, the pH modifying agent,the surfactant and an optional lubricant with the excipient beforecompressing the mixture to form slow release tablets. The excipient maycomprise a physical admix of the gums along with a soluble excipientsuch as compressible sucrose, lactose or dextrose, although it ispreferred to granulate or agglomerate the gums with plain (i.e.,crystalline) sucrose, lactose, dextrose, etc., to form an excipient. Thegranulate form has certain advantages including the fact that it can beoptimized for flow and compressibility; it can be tableted, formulatedin a capsule, extruded and spheronized with an active medicament to formpellets, etc.

The pharmaceutical excipients prepared in accordance with the presentinvention may be prepared according to any agglomeration technique toyield an acceptable excipient product. In wet granulation techniques,the desired amounts of the heteropolysaccharide gum, thehomopolysaccharide gum, and the inert diluent are mixed together andthereafter a moistening agent such as water, propylene glycol, glycerol,alcohol or the like is added to prepare a moistened mass. Next, themoistened mass is dried. The dried mass is then milled with conventionalequipment into granules. Therefore, the excipient product is ready touse.

The pre-manufactured sustained release excipient is preferablyfree-flowing and directly compressible. Accordingly, the excipient maybe mixed in the desired proportion with a therapeutically activemedicament and optional lubricant (dry granulation). Alternatively, allor part of the excipient may be subjected to a wet granulation with theactive ingredient and thereafter tableted. When the final product to bemanufactured is tablets, the complete mixture, in an amount sufficientto make a uniform batch of tablets, is then subjected to tableting in aconventional production scale tableting machine at normal compressionpressure, i.e. about 2000-1600 lbs/sq in. However, the mixture shouldnot be compressed to such a degree that there is subsequent difficultyin its hydration when exposed to gastric fluid.

One of the limitations of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of active is high apharmaceutical formulator may choose to wet granulate the active withother excipients to attain a decent size tablet with the right compactstrength. Usually the amount of filler/binder or excipients needed inwet granulation is less than that in direct compression since theprocess of wet granulation contributes to some extent toward the desiredphysical properties of a tablet.

When the medicament is diltiazem, the average tablet size for roundtablets is preferably about 300 mg to 750 mg and for capsule-shapedtablets about 700 mg to 1000 mg.

The average particle size of the granulated excipient of the presentinvention preferably ranges from about 50 microns to about 400 micronsand preferably from about 185 microns to about 265 microns. The particlesize of the granulation is not narrowly critical, the importantparameter being that the average particle size of the granules, mustpermit the formation of a directly compressible excipient which formspharmaceutically acceptable tablets. The desired tap and bulk densitiesof the granulation of the present invention are normally between from2.5 about 0.3 to about 0.8 g/ml, with an average density of from about0.5 to about 0.7 g/ml. For best results, the tablets formed from thegranulations of the present invention are from about 5 to about 20 kghardness. The average flow of the granulations prepared in accordancewith the present invention are preferably from about 25 to about 40g/sec. Tablets compacted using an Instrumented rotary tablet machinehave been found to possess strength profiles which are largelyindependent of the inert saccharide component. Scanning electronphotomicrographs of largely tablet surfaces have provided qualitativeevidence of extensive plastic deformation on compaction, both at thetablet surface and across the fracture surface, and also show evidenceof surface pores through which initial solvent ingress and solutionegress may occur.

In certain embodiments of the invention, the tablet is coated with asufficient amount of a hydrophobic polymer to render the formulationcapable of further modifying the release of the medicament. Thehydrophobic polymer which is included in the tablet coating may be thesame or different material as compared to the hydrophobic polymericmaterial which is optionally granulated with the sustained releaseexcipient.

In other embodiments of the present invention, the tablet coating maycomprise an enteric coating material in addition to or instead of thehydrophobic polymer coating. Examples of suitable enteric polymersinclude cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, polyvinylacetate phthalate, methacrylic acid copolymer,shellac, hydroxypropylmethylcellulose succinate, cellulose acetatetrimellitate, and mixtures of any of the foregoing. An example of asuitable commercially available enteric material is available under thetrade name Eudragit™ L30D55.

In further embodiments, the dosage form may be coated with a hydrophiliccoating in addition to or instead of the above-mentioned coatings. Anexample of a suitable material which may be used for such a hydrophiliccoating is hydroxypropylmethyl-cellulose (e.g., Opadry® commerciallyavailable from Colorcon, West Point, Pa.).

The coatings may be applied in any pharmaceutically acceptable mannerknown to those skilled in the art. For example, in one embodiment, thecoating is applied via a fluidized bed or in a coating pan. For example,the coated tablets may be dried, e.g., at about 60-70° C. for about 3-4hours in a coating pan. The solvent for the hydrophobic polymer orenteric coating may be organic, aqueous, or a mixture of an organic andan aqueous solvent. The organic solvents may be, e.g., isopropylalcohol, ethanol, and the like, with or without water.

In additional embodiments of the present invention, a support platformis applied to the tablets manufactured in accordance with the presentinvention. Suitable support platforms are well known to those skilled inthe art. An example of suitable support platform is set forth, e.g., inU.S. Pat. No. 4,839,177, hereby incorporated by reference. In thatpatent, the support platform partially coats the tablet, and consists ofa polymeric material insoluble in aqueous liquids. The support platformmay, for example, be designed to maintain its impermeabilitycharacteristics during the transfer of the therapeutically activemedicament. The support platform may be applied to the tablets, e.g.,via compression coating onto part of the tablet surface, by spraycoating the polymeric materials comprising the support platform onto allor part of the tablet surface, or by immersing the tablets in a solutionof the polymeric materials.

The support platform may have a thickness of, e.g., about 2 mm ifapplied by compression, and about 10μ if applied via spray-coating orimmersion-coating. Generally, in embodiments of the invention wherein ahydrophobic polymer or enteric coating is applied to the tablets, thetablets are coated to a weight gain from about 1 to about 20%, and incertain embodiments preferably from about 5% to about 10%.

Materials useful in the hydrophobic coatings and support platforms ofthe present invention include derivatives of acrylic acid (such asesters of acrylic acid, methacrylic acid, and copolymers thereof)celluloses and derivatives thereof (such as ethylcellulose),polyvinylalcohols, and the like.

In certain embodiments of the present invention, the tablet coreincludes an additional dose of the medicament included in either thehydrophobic or enteric coating, or in an additional overcoating coatedon the outer surface of the tablet core (without the hydrophobic orenteric coating) or as a second coating layer coated on the surface ofthe base coating comprising the hydrophobic or enteric coating material.This may be desired when, for example, a loading dose of atherapeutically active agent is needed to provide therapeuticallyeffective blood levels of the active agent when the formulation is firstexposed to gastric fluid. The loading dose of medicament included in thecoating layer may be, e.g., from about 10% to about 40% of the totalamount of medicament included in the formulation.

In preferred embodiments of the invention, the final formulationprovides bi-modal or multi-phasic plasma levels when the medicament isdiltiazem.

In preferred embodiments, when the medicament is diltiazem, theformulations of the invention provide a first time to peak plasmaconcentration (Tmax #1) of the diltiazem in about 4 to about 10 hoursafter oral administration of the dosage form to the patient. In certainpreferred embodiments, the first time to peak plasma concentrationoccurs from about 6 to about 8 hours after oral administration. Inpreferred embodiments, the maximum plasma concentration of diltiazem atthe first Tmax (Cmax #1) is from about 50 to about 100 ng/ml, peradministration of a 240 mg dosage of diltiazem in an oral sustainedrelease dosage form in accordance with the invention.

In further preferred embodiments of the invention, the sustained releasediltiazem formulations provide a second peak plasma concentration (Cmax#2) which occurs in about 10 to about 16 hours after oral administrationof the dosage form to the patient (Tmax #2). In certain preferredembodiments, the second peak plasma concentration (Cmax #2) occurs inabout 12 to about 14 hours after oral administration of the dosage formto the patient (Tmax #2). In preferred embodiments, the maximum plasmaconcentration of diltiazem at Cmax #2 is from about 60 to about 90ng/ml, per 240 mg diltiazem administered over the 24 hour period.

In certain preferred embodiments, the sustained release diltiazemformulations provide a the W₅₀ of Cmax #1 (defined for purposes of thepresent invention as the width of the plasma concentration curve at 50%of the height of the first Cmax (Cmax #1), based on a trough taken atthe Cmin between Cmax #1 and Cmax #2) is from about 0.5 to about 4hours, preferably from about 1 to about 3 hours.

In certain preferred embodiments, the sustained release diltiazemformulations provide a W₅₀ of Cmax #2 (defined for purposes of thepresent invention as the width of the plasma concentration curve at 50%of the height of the second Cmax (Cmax #2), based on a the trough takenat the Cmin between Cmax #1 and Cmax #2) is from about 0.5 to about 8hours, preferably from about 2 to about 6 hours.

In certain preferred embodiments, the sustained release diltiazemformulations of the invention provide a ratio of Cmax #1 to Cmax #2 fromabout 0.5:1 to about 1.5:1; preferably from about 0.7:1 to about 1.2:1.

Based on the dosage of diltiazem in the sustained release oralformulations of the invention, one can easily determine the Cmax #1,Cmax #2, Tmax #1 and Tmax #2 for different dosages of diltiazem over a12 or 24 hour period.

In certain preferred embodiments of the invention when the medicament isoxybutynin, the formulation provides a time to peak plasma concentration(Tmax) of oxybutynin in about 5 to about 15 hours, preferably in about 8to about 12 hours.

Examples of soluble to highly soluble medicaments which are suitable forincorporation in the present invention include antihistamines (e.g.,azatadine maleate, brompheniramine maleate, carbinoxamine maleate,chlorpheniramine maleate, dexchlorpheniramine maleate, diphenhydraminehydrochloride, doxylamine succinate, methdilazine hydrochloride,promethazine, trimeprazine tartrate, tripelennamine citrate,tripelennamine hydrochloride and triprolidine hydrochloride);antibiotics (e.g., penicillin v potassium, cloxacillin sodium,dicloxacillin sodium, nafcillin sodium, oxacillin sodium, carbenicillinindanyl sodium, oxytetracycline hydrochloride, tetracyclinehydrochloride, clindamycin phosphate, clindamycin hydrochloride,clindamycin palmitate hcl, lincomycin hcl, novobiocin sodium,nitrofurantoin sodium, metronidazole hydrochloride); antituberculosisagents (e.g., isoniazid); cholinergic agents (e.g., ambenonium chloride,bethanecol chloride, neostigmine bromide, pyridostigmine bromide);antimuscarinics (e.g., anisotropine methylbromide, clidinium bromide,dicyclomine hydrochloride, glycopyrrolate; hexocyclium methylsulfate,homatropine methylbromide, hyoscyamine sulphate, methantheline bromide,hyoscine hydrobromide, oxyphenonium bromide, propantheline bromide,tridihexethyl chloride); sympathomimetics (e.g., bitolterol mesylate,ephedrine, ephedrine hydrochloride, ephedrine sulphate, orciprenalinesulphate, phenylpropanolamine hydrochloride, pseudoephedrinehydrochloride, ritodrine hydrochloride, salbutamol sulphate, terbutalinesulphate); sympatholytic agents (e.g., phenoxybenzamine hydrochloride);miscellaneous autonomic drugs (e.g., nicotine); iron preparations (e.g.,ferrous gluconate, ferrous sulphate); haemostatics (e.g., aminocaproicacid); cardiac drugs (e.g., acebutolol hydrochloride, disopyramidephosphate, flecamide acetate, procainamide hydrochloride, propranololhydrochloride, quinidine gluconate, timolol maleate, tocainidehydrochloride, verapamil hydrochloride); antihypertensive agents (e.g.,captopril, clonidine hydrochloride, hydralazine hydrochloride;mecamylamine hydrochloride, metoprolol tartrate); vasodilators (e.g.,papaverine hydrochloride); non-steroidal anti-inflammatory agents (e.g.,choline salicylate, magnesium salicylate, meclofenamate sodium, naproxensodium, tolmetin sodium); anticonvulsants (e.g., phenobarbital sodium,phenyloin sodium, troxidone, ethosuximide, valproate sodium);tranquilizers (e.g., acetophenazine maleate, chlorpromazinehydrochloride, fluphenazine hydrochloride, prochlorperazine edisylate,promethazine hydrochloride, thioridazine hydrochloride,trifluoroperazine hydrochloride, lithium citrate, molindonehydrochloride, thiothixine hydrochloride); stimulants (e.g.,benzamphetamine hydrochloride, dextro amphetamine sulphate,dextroamphetamine phosphate, diethylpropion hydrochloride, fenfluraminehydrochloride, methamphetamine hydrochloride, methylphenidatehydrochloride, phendimetrazine tartrate, phenmetrazine hydrochloride,caffeine citrate); barbiturates (e.g., amylobarbital sodium,butabarbital sodium, secobarbital sodium); sedatives (e.g., hydroxyzinehydrochloride, methprylon); expectorants (e.g., potassium iodide);antiemetics (e.g., benzaquinamide hydrochloride, metoclopropamidehydrochloride, trimethobenzamide hydrochloride); gastro-intestinal drugs(e.g., ranitidine hydrochloride); heavy metal antagonists (e.g.,penicillamine, penicillamine hydrochloride); antithyroid agents (e.g.,methimazole); genitourinary smooth muscle relaxants (e.g., flavoxatehydrochloride); vitamins (e.g., thiamine hydrochloride, ascorbic acid);unclassified agents (e.g., amantadine hydrochloride, colchicine,etidronate disodium, leucovorin calcium, methylene blue, potassiumchloride, pralidoxime chloride. This list is not meant to be exclusive.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Examples 1-2 Effect of Drug:Gum Ratio in Formulation

In Example 1-2, sustained release excipients in accordance with thepresent invention are first prepared, the medicament (in this casediltiazem) and the pH modifying agent (in this case being fumaric acid)being added subsequently, and the final mixture then being tableted.

The sustained release excipient is prepared by dry blending therequisite amounts of xanthan gum, locust bean gum, and dextrose in ahigh speed mixer/granulator for 3 minutes. While runningchoppers/impellers; water is added to the dry blended mixture, andgranulated for another 3 minutes. The granulation is then dried in afluid bed dryer to a LOD (loss on drying) of less than about 10% byweight (e.g., 4-7% LOD). The granulation is then milled using 20 meshscreens and dispensed into a granulator. The ingredients of thegranulations of Examples 1-2 are set forth in Table 1 below:

TABLE 1 PREPARATION OF SUSTAINED-RELEASE EXCIPIENT Component Amount(%) - Ex. 1 Amount (%) - Ex. 2 1. Xanthan Gum 20 12 2. Locust Bean Gum30 18 3 Dextrose 50 70 4 Water 30 25

Next, the desired amount of diltiazem, fumaric acid and a suitableamount of water are mixed for 5 minutes with an impeller type mixer toform a slurry. The slurry is then added to the sustained releaseexcipient over a 1 minute interval in the granulator, with the impellerrunning on low speed. Next, the mixture is granulated for 2 minutes withthe chopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is added,and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 768 mg. Theingredients of the tablets of Examples 1-2 are set forth in Table 2below:

TABLE 2 TABLET FORMULATION - EXAMPLES 1-2 Component Amount (%) Amount(mg/tab) 1. Sustained-Release Excipient 52.1 400.0 2. Diltiazem 31.3240.0 3. Fumaric Acid 5.2 40.0 4 Sodium Laurel Sulfate 10.4 80.0 5Pruv ® (Sodium Stearyl Fumarate) 1.0 8.0 6. Water* 27.5 0.0 *Removedduring processing

The final tablets have a tablet weight of 768.0 mg and a hardness of 15Kp.

Dissolution tests were then carried out on the tablets of Examples 1-2in 900 ML water M an automated USP dissolution apparatus (Paddle typeII, 100 rpm), and the amount of drug released was analyzed via UVanalysis. The in-vitro dissolution results are set forth in FIG. 1 andin Table 3 below.

TABLE 3 Time (hr) Ex. 1 (% dissolved) Ex. 2 (% dissolved) 0 0.0 0.0 113.4 8.3 2 19.0 12.4 4 28.4 18.4 8 40.9 29.0 12 52.3 38.2 16 63.1 44.420 70.1 49.9 24 78.2 55.3

From the results provided in FIG. 1 and Table 3, it is evident that therate of release of diltiazem is slower as the amount of gum in theformulations is increased.

Examples 3-4 Effect of Gum:Dextrose Ratio

In Examples 3-4, a sustained release excipient is prepared in accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 3 and 4 are set forth in table 4below:

TABLE 4 Component Amount (%) - Ex. 1 Amount (%) - Ex. 2 1 Xanthan Gum 1220 2 Locust Bean Gum 18 30 3 Dextrose 70 50 4 Water* 25 35 *removedduring processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and the sustained releaseexcipient are placed in a granulator and mixed for 3 minutes at lowspeed. Water is added over a 2 minute interval while the impeller isrunning at low speed (additional water and granulation time may be usedto form proper granules). The resultant granules are then dried in afluid bed dryer until LOD is less than 5% and milled with hammer forwardat 2000-3000 rpm using screen #0050. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co.) is added,and the mixture is blended for another 5 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg. Theingredients of the tablets of Examples 3-4 are set forth in Table 5below:

TABLE 5 TABLET FORMULATION - EXAMPLES 3-4 Component Amount (%) Amount(mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2. Diltiazem 32.0240.0 3. Fumaric Acid 8.0 60.0 4. Sodium Laurel Sulfate 5.3 40.0 5.Pruv ® (Sodium Stearyl Fumarate) 1.3 10.0 6. Water* 27.5 0.0 *Removedduring processing

The final tablets have a tablet weight of 750.0 mg and a hardness of 15Kp

Dissolution tests were then carried out on the tablets of Examples 3-4in 250 ML buffer (ph 6) in an automated USP dissolution apparatus(Paddle type III, 15 CPM), and the amount of drug released was analyzedvia UV analysis. The in-vitro dissolution results are set forth in FIG.2 and in Table 6 below:

TABLE 6 Time (hr) Ex. 3 (% dissolved) Ex. 4 (% dissolved) 0 0.0 0.0 120.1 14.3 3 36.5 25.2 8 64.7 45.5 12 88.3 57.2 16 102.2 67.4 24 103.686.2

From the results provided in FIG. 2 and Table 6, it is evident that asthe amount of gum relative to the amount of dextrose is increased, acorresponding decrease in drug release is observed.

Examples 5-6 Effect of Surfactant Type

In Examples 5-6, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 5 and 6 are set forth in table 7below:

TABLE 7 Component Amount (%) - Ex. 5-6 1 Xanthan Gum 12 2 Locust BeanGum 18 3 Dextrose 70 4 Water* 25 *removed during processing

Thereafter, diltiazem tablets are prepared as follow:

The desired amount of diltiazem, fumaric acid and a suitable amount ofwater are mixed for 5 minutes with an impeller type mixer to form aslurry. The slurry is then added to the sustained release excipient overa 1 minute interval in the granulator, with the impeller running on lowspeed. Next, the mixture is granulated for 2 minutes with the chopperand impeller on high speed (additional water and granulation time may beused to form proper granules). The resultant granules are then dried ina fluid bed dryer until LOD is less than 5% and milled with hammerforward at 2000-3000 rpm. The milled granulation of Example 5 is thenplaced in a V-Blender with sodium lauryl sulfate, and the milledgranulation of Example 6 is placed in a V-Blender with docusate sodiumand blended for 10 minutes. A suitable tableting lubricant (Pruv®,sodium stearyl fumarate, NF, commercially available from PenwestPharmaceuticals Co. is then added to each example, and the mixtures areblended for another 3 minutes. The resultant granulations are thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 848 mg. The ingredients of the tablets ofExamples 5-6 are set forth in Table 8 below:

TABLE 8 TABLET FORMULATION - EXAMPLES 5-6 Amount Amount Component (%)(Ex. 5) (%) (Ex. 6) 1. Sustained-Release Excipient 47.2 47.2 2.Diltiazem 28.3 28.3 3. Fumaric Acid 14.2 14.2 4. Sodium Laurel Sulfate9.4 N/A 5 Docusate Sodium N/A 9.4 6 Pruv ® (Sodium Stearyl Fumarate) 0.90.9 7. Water* 26.5 26.5 Amount Amount (mg/tab) (mg/tab) Component (Ex.5) (Ex. 6) 1 Sustained-Release Excipient 400.0 400.0 2 Diltiazem 240.0240.0 3 Fumaric Acid 120.0 120.0 4 Sodium Laurel Sulfate 80.0 N/A 5Docusate Sodium N/A 80.0 6 Pruv ® (Sodium Stearyl Fumarate) 8.0 8.0*Removed during processing

The final tablets have a tablet weight of 848.0 mg. and a hardness of 15Kp.

Dissolution tests were then carried out on the tablets of Examples 1-2.The dissolution tests were conducted in 900 ML water in an automated USPdissolution apparatus (Paddle type II, 100 rpm), and the amount of drugreleased was analyzed via UV analysis. The in-vitro dissolution resultsare set forth in FIG. 3 and in Table 9 below.

TABLE 9 Time (hr) Ex. 5 (% dissolved) Ex. 6 (% dissolved) 0 0.0 0.0 114.0 12.2 2 19.3 18.9 4 31.3 29.8 8 49.5 47.6 12 62.7 61.4 16 77.0 73.020 88.5 83.5 24 98.6 89.2

From the results provided in FIG. 3 and Table 9, it is evident that therate of release of diltiazem is similar for equivalent ratios of sodiumlauryl sulfate and docusate sodium. However, the formulation did processbetter with sodium lauryl sulfate.

Examples 7-8 Effect of Surfactant Level

In Examples 7-8, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples. 7 and 8 are set forth in table10 below:

TABLE 10 Component Amount (% -) Ex. 7-8 1. Xanthan Gum 12 2. Locust BeanGum 18 3. Dextrose 70 4. Water* 25 *Removed during processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and a suitable amount ofwater are mixed for 5 minutes with an impeller type mixer to form aslurry. The slurry is then added to sustained release excipient over a 1minute interval in the granulator, with the impeller running on lowspeed. Next, the mixture is granulated for 2 minutes with the chopperand impeller on high speed (additional water and granulation time may beused to form proper granules). The resultant granules are then dried ina fluid bed dryer until LOD is less than 5% and milled with hammerforward at 2000-3000 rpm. The milled granulation is then placed in aV-Blender with sodium lauryl sulfate and blended for 10 minutes. Asuitable tableting lubricant (Pruv®, sodium stearyl fumarate, NF,commercially available from Penwest Pharmaceuticals Co. is then added,and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 768 mg. Theingredients of the tablets of Examples 7-8 are set forth in Table 11below:

TABLE 11 TABLET FORMULATION - EXAMPLES 7-8 Amount Amount Component (%)(Ex. 7) (%) (Ex. 8) 1. Sustained-Release Excipient 52.1 54.9 2.Diltiazem 31.3 33.0 3. Fumaric Acid 5.2 5.5 4. Sodium Laurel Sulfate10.4 5.5 5 Pruv ® (Sodium Stearyl Fumarate) 1.0 1.1 6. Water* 27.5 27.5Amount Amount (mg/tab) (mg/tab) Component (Ex. 7) (Ex. 8) 1.Sustained-Release Excipient 400.0 400.0 2. Diltiazem 240.0 240.0 3.Fumaric Acid 40.0 40.0 4. Sodium Laurel Sulfate 80.0 40.0 5. Pruv ®Sodium Stearyl Fumarate 8.0 8.0 *Removed during processing

The final tablets of Example 7 have a tablet weight of 768.0 mg. and ahardness of 15 Kp.

The final tablets of Example 8 have a tablet weight of 728.0 mg. and ahardness of 15 Kp.

Dissolution tests were then carried out on the tablets of Examples 7-8.The dissolution tests were conducted in 900 ML water in an automated USPdissolution apparatus (Paddle type II, 100 rpm), and the amount of drugreleased was analyzed via UV analysis. The results are set forth in FIG.4 and Table 12 below:

TABLE 12 Time (hr) Ex. 7 (% Dissolved) Ex. 8 (% Dissolved) 0 0.0 0.0 113.4 18.5 2 19.0 28.2 4 28.4 40.1 8 40.9 56.1 12 52.3 67.6 16 63.1 77.720 70.1 83.8 24 78.2 90.5

From the results provided in FIG. 4 and Table 12, it is evident that thedissolution rate of diltiazem is inversely related to the surfactantlevel.

Examples 9-10 Effect of Fumaric Acid Level

In Examples 9-10, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 9 and 10 are set forth in table13 below:

TABLE 13 Component Amount (%) - Ex. 9-10 1. Xanthan Gum 12 2. LocustBean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and a suitable amount ofwater are mixed for 5 minutes with an impeller type mixer to form aslurry. The slurry is then added to sustained release excipient over a 1minute interval in the granulator, with the impeller running on lowspeed. Next, the mixture is granulated for 2 minutes with the chopperand impeller on high speed (additional water and granulation time may beused to form proper granules). The resultant granules are then dried ina fluid bed dryer until LOD is less than 5% and milled with hammerforward at 2000-3000 rpm. The milled granulation is then placed in aV-Blender with sodium lauryl sulfate and blended for 10 minutes. Asuitable tableting lubricant (Pruv®, sodium stearyl fumarate, NF,commercially available from Penwest Pharmaceuticals Co. is then added,and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 848 mg. Theingredients of the tablets of Examples 9-10 are set forth in Table 14below:

TABLE 14 TABLET FORMULATION - EXAMPLES 9-10 Amount (%) Amount (%)Component (Ex. 9) (Ex. 10) 1. Sustained-Release Excipient 47.2 52.1 2.Diltiazem 28.3 31.3 3. Fumaric Acid 14.2 5.2 4. Sodium Laurel Sulfate9.4 10.4 5. Pruv ® (Sodium Stearyl Fumarate) 0.9 1.0 *Sodium StearylFumarate 6. Water* 26.5 26.5 *Removed during processing Amount (mg/tab)Amount (mg/tab) Component (Ex. 9) (Ex. 10) 1. Sustained-ReleaseExcipient 400.0 400.0 2. Diltiazem 240.0 240.0 3. Fumaric Acid 120.040.0 4. Sodium Laurel Sulfate 80.0 80.0 5. Pruv ®* 8.0 8.0 *SodiumStearyl Fumarate

The final tablets in Example 9 have a weight of 848.0 mg. and a hardnessof 15 Kp.

The final tablets in Example 10 have a weight of 768 mg. and a hardnessof 15 Kp.

Dissolution tests were then carried out on the tablets of Examples 9-10.The dissolution tests were conducted in 900 ML water in an automated USPdissolution apparatus (Paddle type II, 100 rpm), and the amount of drugreleased was analyzed via UV analysis. The results are set forth in FIG.5 and Table 15 below:

TABLE 15 Time (hr) Ex. 9 (% Dissolved) Ex. 10 (% Dissolved) 0 0.0 0.0 114.0 13.4 2 19.3 19.0 4 31.3 28.4 8 49.5 40.9 12 62.7 52.3 16 77.0 63.120 88.5 70.1 24 98.6 78.2

From the results provided in FIG. 5 and Table 15, it is evident that byincreasing the amount of fumaric acid in the formulation, the releaserate increases.

Examples 11-12 Extra-Granular Addition of Drug

In Examples 11-12, a sustained release excipient is prepared accordancewith the procedure, set forth in Examples 1 and 2. The ingredients ofthe sustained release excipient of Examples 11 and 12 are set forth intable 16 below:

TABLE 16 Component Amount (%) - Ex. 11-12 1. Xanthan Gum 12 2. LocustBean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during processing

Thereafter, diltiazem tablets are prepared as follows:

In Example 11, the desired amount of diltiazem, fumaric acid and asuitable amount of water are mixed for 5 minutes with an impeller typemixer to form a slurry. The slurry is then added to sustained releaseexcipient over a 1 minute interval in the granulator, with the impellerrunning on low speed. Next, the mixture is granulated for 2 minutes withthe chopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is thenadded, and the mixture is blended for another 3 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 848 mg.

In Example 12, a portion of diltiazem, fumaric acid and a suitableamount of water are mixed for 5 minutes with an impeller type mixer toform a slurry. The slurry is then added to sustained release excipientover a 1 minute interval in the granulator, with the impeller running onlow speed. Next, the mixture is granulated for 2 minutes with thechopper and impeller on high speed (additional water and granulationtime may be used to form proper granules). The resultant granules arethen dried in a fluid bed dryer until LOD is less than 5% and milledwith hammer forward at 2000-3000 rpm. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and the remainingamount of diltiazem and blended for 10 minutes. A suitable tabletinglubricant (Pruv®, sodium stearyl fumarate, NF, commercially availablefrom Penwest Pharmaceuticals Co. is then added, and the mixture isblended for another 3 minutes. The resultant granulation is thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 848 mg. The ingredients of the tablets ofExamples 11-12 are set forth in Table 17 below:

TABLE 17 TABLET FORMULATION - EXAMPLES 11-12 Amount (%) Amount (%)Component (Ex. 11) (Ex. 12) 1. Sustained-Release Excipient 47.2 47.2 2.Diltiazem (granular) 28.3 18.4 3. Diltiazem (extragranular) N/A 9.9 4.Fumaric Acid 14.2 14.2 5. Sodium Laurel Sulfate 9.4 9.4 6. Pruv ®(Sodium Stearyl Fumarate) 0.9 0.9 7. Water* 26.5 25.0 *Removed duringprocessing Amount (mg/tab) Amount (mg/tab) Component (Ex. 11) (Ex.12) 1. Sustained-Release Excipient 400.0 400.0 2. Diltiazem (granular)240.0 156.0 3. Diltiazem (extragranular) N/A 84.0 4. Fumaric Acid 120.0120.0 5. Sodium Laurel Sulfate 80.0 80.0 6. Pruv ® (Sodium Stearyl 8.08.0 Fumarate)

The final tablets of Example 11 have a weight of 848.0 mg. and ahardness of 15 Kp.

The final tablets of Example 12 have a weight of 848.0 mg. and ahardness of 15 Kp.

Dissolution tests were then carried out on the tablets of Examples11-12. The dissolution tests were conducted in 900 ML water in anautomated USP dissolution apparatus (Paddle type II, 100 rpm), and theamount of drug released was analyzed via UV analysis. The results areset forth in FIG. 6 and Table 18 below:

TABLE 18 Time (hr) Ex. 11 (% Dissolved) Ex. 12 (% Dissolved) 0 0.0 0.0 114.2 32.6 2 19.3 35.5 4 31.3 48.7 8 49.5 66.4 12 62.7 78.5 16 77.0 85.220 88.5 89.2 24 98.6 94.6

From the results provided in FIG. 6 and Table 18, it is shown that theaddition of diltiazem extragranularly produces an initial burst ofapproximately 35%. It is evident that the addition of a percentage ofthe drug extra-granularly provides an initial rapid release, as alsodemonstrated by FIG. 7 which depicts the % release rate of diltiazemfrom the dosage forms of Examples 11 and 12 over time.

Examples 13-18 Effect of Coating Tablets with Eudragit L30D55 NaOH(Methacrylic Acid Copolymer Aqueous Dispersion)

In Examples 13-18, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 13-18 are set forth in table 19below:

TABLE 19 Component Amount (%) - Ex. 13-18 1. Xanthan Gum 12 2. LocustBean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and the sustained releaseexcipient are mixed in a granulator for 3 minutes at low speed. Asuitable amount of water is then added over a 2 minute interval with theimpeller running at low speed. The resultant slurry is then granulatedfor 7.5 minutes with the chopper and impeller on high speed (additionalwater and granulation time may be used to form proper granules). Theresultant granules are then dried in a fluid bed dryer until LOD is lessthan 5% and milled with hammer forward at 2000-3000 rpm using screen#0050. The milled granulation is then placed in a V-Blender with sodiumlauryl sulfate and blended for 10 minutes. A suitable tabletinglubricant (Pruv®, sodium stearyl fumarate, NF, commercially availablefrom Penwest Pharmaceuticals Co. is then added, and the mixture isblended for another 5 minutes. The resultant granulation is thenCompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 750 mg.

The ingredients of the tablets of Examples 13-18 are set forth in Table20 below:

TABLE 20 TABLET FORMULATION - EXAMPLES 13-18 Component Amount (%) 1.Sustained-Release Excipient 53.3 2. Diltiazem (granular) 32.0 3. FumaricAcid 8.0 4. Sodium Laurel Sulfate 5.3 5. Pruv ® (Sodium StearylFumarate) 1.3 6. Water* 27.0 *Removed during processing Component Amount(mg/tab) 1. Sustained-Release Excipient 400.0 2. Diltiazem (granular)240.0 3. Fumaric Acid 60.0 4. Sodium Laurel Sulfate 40.0 5. Pruv ®(Sodium Stearyl Fumarate) 10.0

The final tablets have a tablet weight of 750.0 mg. and a hardness of 15Kp.

The core tablets were then coated with an aqueous dispersion of EudragitL30D55 w/ NaOH, e.g., to a weight gain of 3%, 5%, 7%, and 9% (Examples15-18, respectively) based on the weight of the whole tablet.

The aqueous dispersion was prepared by the following procedure:

1.0N sodium hydroxide solution is prepared by adding 4.0 g of sodiumhydroxide to 50 ml purified water in a volumetric flask and stirring for5-15 minutes. Purified water is then added to the necessary volume andmixed again.

The talc suspension is prepared by slowly adding 9.31 g triethyl citrateto 202.54 g purified water while stirring. While continuing to stir,22.2 g talc is added to the container over a 3 minute interval. Thecontainer is stirred until a suspension is formed.

Eudragit suspension is then prepared by passing the Eudragit through a#40 mesh sieve and weighing out 294.52 g. Using a dropper, 1.78 g of1.0N sodium hydroxide solution is added to the Eudragit while stirring.The mixture is stirred for 30-60 minutes.

While stirring the Eudragit suspension, the talc suspension is addedover a 5 minute period and stirred for 30-60 minutes.

Dissolution tests were carried out on the tablets of Examples 13-18. Thedissolution tests were conducted in 250 ML buffer (ph 6) in an automatedUSP dissolution apparatus (Paddle type III, 15 CPM), and the amount ofdrug released was analyzed via UV analysis.

The results are set forth in FIG. 8 and Table 21 below:

TABLE 21 Time Ex. 13 Ex. 14 Ex.15 (hr) Lot A (no coating) Lot B (nocoating) Lot A (3% coating) 0 0.0 0.0 0.0 1 18.4 18.0 5.4 3 32.6 32.816.0 8 59.8 60.2 48.9 12 80.5 77.9 68.2 16 92.3 93.9 89.6 24 93.7 98.499.0 Time Ex. 16 Ex. 17 Ex. 18 (hr) Lot B (coating 5%) Lot B (coating7%) Lot B (coating 9%) 0 0.0 0.0 0.0 1 1.9 0.4 0.4 3 13.8 11.1 8.9 844.1 36.3 27.5 12 63.4 54.4 41.8 16 82.4 77.7 56.8 24 98.3 99.6 84.6

From the results provided in FIG. 8 and Table 21, it is evident that asthe amount y weight) of the coating increases, the release ratedecreases.

Examples 19-20 Effect of Coating Tablets with EudragitRS30D/RL30D(50/50) (Ammonio-methacrylic Acid Copolymer AqueousDispersion)

In Examples 19-20, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 19 and 20 are set forth in table22 below:

TABLE 22 Component Amount (%) - Ex. 19-20 1. Xanthan Gum 12 2. LocustBean Gum 18 3. Dextrose 70 4. Water* 25 *removed during processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and the sustained releaseexcipient are mixed in a granulator for 3 minutes at low speed. Asuitable amount of water is then added over a 2 minute interval with theimpeller running at low speed. The resultant slurry is then granulatedfor 6 minutes with the chopper and impeller on high speed (additionalwater and granulation time may be used to form proper granules). Theresultant granules are then dried in a fluid bed dryer until LOD is lessthan 5% and milled with hammer forward at 2000-3000 rpm using screen#0050. The milled granulation is then placed in a V-Blender with sodiumlauryl sulfate and blended for 10 minutes. A suitable tabletinglubricant (Pruv®, sodium stearyl fumarate, NF, commercially availablefrom Penwest Pharmaceuticals Co. is then added, and the mixture isblended for another 3 minutes. The resultant granulation is thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 50 mg.

The ingredients of the tablets of Examples 19-20 are set forth in FIG. 9and Table 23 below:

TABLE 23 TABLET FORMULATION - EXAMPLES 19-20 Component Amount (%) Amount(mg/tb) 1. Sustained-Release Excipient 53.3 400.0 2. Diltiazem(granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium Laurel Sulfate5.3 40.0 5. Pruv ® (Sodium Stearyl Fumarate). 1.3 10.0 6. Water* 27.00.0 *Removed during processing

The final tablets have a weight of 750.0 mg. and a hardness of Kp 15.

The core tablet was then coated with an aqueous dispersion of EudragitRS30D/RL30D(50/50) to a weight gain of 8%, based on the weight of thewhole tablet.

The aqueous dispersion was prepared by the following procedure:

The Eudragit RS/RL suspension is prepared by mixing 100 g of Eudragit RSwith 100 g of Eudragit RL.

Talc suspension is prepared by slowly adding 12.0 g triethyl citrate to338.0 g purified water while stirring. While continuing to stir, 50.0 gtalc is added to the container over a 3 minute interval. The containeris stirred until a suspension is formed.

While stirring the Eudragit suspension, the talc suspension is thenadded over a 5 minute period. The resultant mixture is stirred for 30-60minutes and screened through a 40 mesh sieve.

Dissolution tests were carried out on the tablets of Examples 19-20. Thedissolution tests were conducted in 900 ML of 0.1N HCL in an automatedUSP dissolution apparatus (Paddle type II, 100 rpm), and the amount ofdrug released was analyzed via UV analysis. The results are set forth inFIG. 9 and Table 24 below:

TABLE 24 Time (hr) Ex. 19 (8% coating) Ex. 20 (No coating) 0 0.0 0.0 121.5 0.5 3 41.3 11.6 5 55.9 24.4 8 74.3 46.4 10 84.8 57.5 12 91.9 64.914 95.1 72.2 16 96.2 77.6 20 96.0 87.5 24 96.1 91.3

From the results provided in FIG. 9 and Table 24, it is evident that thecoating-decreased the release rate.

Examples 21-23 Effect of Coating Tablets with Ethylcellulose

In Examples 21-23, a sustained release excipient is prepared accordancewith the procedure set forth in Examples 1 and 2. The ingredients of thesustained release excipient of Examples 21-23 are set forth in table 25below:

TABLE 25 Component Amount (%) - Ex. 21-23 1. Xanthan Gum 12 2. LocustBean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during processing

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and the sustained releaseexcipient are mixed in a granulator for 3 minutes at low speed. Asuitable amount of water is then added over a 2 minute interval with theimpeller running at low speed. The resultant slurry is then granulatedfor 3 minutes with the chopper and impaler on high speed (additionalwater and granulation time may be used to form proper granules). Theresultant granules are then dried in a fluid bed dryer until LOD is lessthan 5% and milled with hammer forward at 2000-3000 rpm using screen#0050. The milled granulation is then placed in a V-Blender with sodiumlauryl sulfate and blended for 10 minutes. A suitable tabletinglubricant (Pruv®, sodium stearyl Fumarate, NF, commercially availablefrom Penwest Pharmaceuticals Co. is then added, and the mixture isblended for another 3 minutes. The resultant granulation is thencompressed into tablets using a capsule shaped punch. This final mixtureis tableted to approximately 750 mg.

The ingredients of the tablets of Examples 21-23 are set forth in Table26 below:

TABLE 26 TABLET FORMULATION - EXAMPLES 21-23 Component Amount (%) Amount(mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2. Diltiazem(granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium Laurel Sulfate5.3 40.0 5. Pruv ® (Sodium Stearyl Fumarate) 1.3 10.0 6. Water* 29.0 0.0

The final tablets have a tablet weight of 750.0 mg. and a hardness of 15Kp.

The core tablet was then coated with an aqueous dispersion ofEthylcellulose/Opadry(80/20) to a weight gain of 4% and 6% (Examples 22and 23, respectively) based on the whole weight of the tablet. Theaqueous dispersion was prepared by the following procedure:

First, 60 g of Opadry is mixed with 340 g of water in a suitablecontainer. While continuing to mix, 944 g Ethylcellulose is added to theOpadry dispersion. The resultant mixture is stirred for 30-60 minutes.

Dissolution tests were then carried out on the tablets of Examples 1-2.The dissolution tests are conducted in 250 ML of buffer (ph 6) in anautomated USP dissolution apparatus (Paddle type UT, 15 CPM), and theamount of drug released was analyzed via UV analysis. The results areset forth in FIG. 10 and Table 27 below:

TABLE 27 Ex. 21 Ex. 22 Ex. 23 Time (hr) (No Coating) (4% Coating) (6%Coating) 0 0.0 0.0 0.0 1 8.8 4.1 0.5 3 39.1 29.8 1 2.6 8 69.0 61.2 58.212 85.1 86.7 95.5 16 106.6 99.8 101.3 24 107.0 101.9 101.5

From the results provided in FIG. 10 and Table 27, it is evident that asthe amount of coating increased, the release rate decreased.

Examples 24-25 Effect of Excipient Addition Outside Granulation

In Examples 24-25, a sustained release excipient is prepared inaccordance with the procedure in Examples 1 and 2. The ingredients ofthe sustained release excipient of Examples 24 and 25 are set forth inTable 28 below:

TABLE 28 Component Amount (%) Ex. 25 Amount (%) Ex. 26 1. xanthan Gum 1212 2. Locust Bean Gum 18 18 3. Dextrose 70 70 4. Water* 25 25 *Removedduring processing.

Next, tablets were manufactured in accordance with the ingredients ofTable 29 and the procedure that follows:

TABLE 29 (%) mg/tab (%) mg/tab Component Ex. 24 Ex. 24 Ex. 25 Ex 25 1.Sustained Release Excipient 49.2 400.0 53.3 400.0 2. Diltiazem HCL 19.2156.0 32.0 240.0 (Intragranular) 3. Diltiazem HCI 10.3 84.0 N/A N/A(Extra granular) 4. Fumaric Acid 14.8 120.0 8.0 60.0 5. Surfactant (SLS)4.9 40.0 5.3 40.0 6. Sodium Stearyl Fumarate, NF 1.6 13.0 1.3 10.0 7.Water* 27.0 0.0 27.0 0.0 *Removed during processing

The final tablets of Example 24 have a tablet weight of 813.0 mg. and ahardness of 15 Kp.

The final tablets of Example 25 have a tablet weight of 750.0 mg. and ahardness of 15 Kp.

The procedure for preparing the formulations of Examples 24-25 is a sfollows:

The desired amount of (1), (2), and (4) are dispensed into a granulatorand mixed for 3 minutes at low speed; while running the impeller at lowspeed, (7) is added over a 2 minute interval; the mixture is granulatedfor 7.5 minutes with the chopper and the impeller on high speed(additional water and granulation time may be used to form propergranules); the granulated mixture is dried in a fluid bed dryer untilthe LOD is less than 5%; the dried granulation is milled with the hammerforward at 2000-3000 rpm using screen #0050; the milled granulation and(5) or (3&5) are placed in a V-Blender and blended for 10 minutes; (6)is 30, added to the V-Blender and blended for 5 minutes. The finalmixture is compressed into tablets using a capsule shaped punch.

The Eudragit® L30D55 w/ NaOH Coating Dispersion was prepared as follows:

A. 1.0N Sodium Hydroxide solution was prepared by adding 4.0 g of SodiumHydroxide to a 100 ml volumetric flask; then 50 ml of Purified water anda magnetic stir bar were added into the flask and the contents of theflask were mixed for 5-15 minutes; the stir bar was removed and thevolume was Q.S. and mixed.

B. Talc suspension was prepared by weighing 202.54 g of Purified waterin a suitable container; 9.31 g of Triethyl Citrate was slowly addedwhile the Purified water was stirred; then 22.22 g of Talc was addedover a 2 minute interval to the container while the mixture was stirred(the mixture was stirred until a suspension formed).

C. Eudragit® L30D55 Suspension was prepared by passing the Eudragit®L30D55 through a #40 mesh sieve; 294.52 g of sieved Eudragit® L30D55 wasweighed and placed into a suitable container; using a dropper, 3.56 g ofthe 1.0N Sodium Hydroxide solution (StepA) was added while the mixturewas stirred; the mixture was stirred for 30-60 minutes.

D. The final Coating Suspension was prepared by stirring the Eudragit®L30D55 Suspension (Step C) while Talc suspension (step B) was added overa 5 minute period; the mixture was stirred for 30-60 minutes.

The tablets were coated for a weight gain of 4% based on the wholeweight of the tablet. The tablets were encapsulated by placing thecoated tablets into clear gelatin capsules.

Plasma Profile of Example 24

In-vivo studies were performed with the tablet of Example 24 using a twoway randomized, open label crossover design in healthy volunteers, 12subjects for each, and they were dosed in the fasted state and comparedwith CARDIZEM CD®. The results are set forth in FIG. 11 and in Tablet 30below:

TABLE 30 Time (hours) Ex. 24 Fasted (ng/ml) Cardizem-CD Fasted (ng/ml) 00.00 0.00 1 0.65 0.00 2 4.72 0.00 4 31.02 19.65 6 62.45 83.08 7 63.2760.98 8 65.45 50.79 9 64.20 42.52 10 65.39 38.43 12 77.30 42.56 14 82.8652.58 15 81.91 56.40 16 80.17 57.48 18 70.09 57.73 20 57.59 51.97 2442.21 43.48 30 24.82 28.73 36 10.97 12.8 48 2.55 3.78

Ratio

The ratio of the area are under the curve between Example 24 andCARDIZEM CD® 240 mg was 1.16:1. The ratio of the average Cmax betweenExample 25 and Cardizem CD 240 mg was 1.16:1.

Outcome

FIG. 11 and Example 24 demonstrated a Bi-Modal plasma level in-vivo, theCARDIZEM CD® also demonstrated Bi-Modal plasma levels by the mixture oftwo differently processed bead formulations.

Plasma Profile of Example 25

In-vivo studies were performed with the tablets of Example 25 using atwo way randomized, open label crossover design in healthy volunteers,12 subjects for each and they were dosed in the fasted state andcompared with CARDIZEM CD®. The results set forth in FIG. 12 and inTable 31 below:

TABLE 31 Time (hours) EXAMPLE Fasted (ng\ml) Cardizem-CD Fasted (ng\ml)0 0.00 0.00 1 0.30 0.05 2 6.55 0.40 4 35.43 5.48 6 77.71 66.02 7 76.9158.31 8 70.88 47.29 9 66.18 39.31 10 64.98 35.51 12 71.90 38.55 14 65.4841.66 15 62.72 47.32 16 60.60 49.73 18 48.87 51.16 20 38.95 45.75 2433.10 41.44 30 20.93 28.40 36 10.14 14.88 48 2.52 4.00

The ratio of the area under the curve between Example 25 and Cardizem CD240 mg. was 1.16:1. The ratio of the average Cmax between Example 25 andCardizem CD. 240 mg. was 1.26:1:

Outcome

FIG. 12 and Example 25 demonstrated a Bi-Modal plasma level in-vivo,CARDIZEM CD® also demonstrated Bi-Modal plasma levels by the mixture oftwo differently processed bead formulations.

Examples 26 and 27 Effect of Different Excipients

In Examples 26 and 27, a sustained release excipient is prepared inaccordance with the procedure set froth in Examples 1 and 3. Theingredients of the sustained release excipient of Examples 25 and 26 areset forth in Table 32 below:

TABLE 32 Component (%) Example 26 Example 27 1. Xanthan Gum 12 25 2.Locust Bean Gum 18 25 3. Calcium Sulfate N/A 10 4. Ethyl Cellulose N/A 5 5. Dextrose 70 35 6. Water* 25 N/A 7. Ethanol* N/A 20 *Removed duringprocessing

Formulation Table 33

Thereafter, diltiazem tablets are prepared as follows:

The desired amount of diltiazem, fumaric acid and the sustained releaseexcipient are placed in a granulator and mixed for 3 minutes at lowspeed. Water is added over a 2 minute interval while the impeller isrunning at low speed (additional water and granulation time may be usedto form proper granules). The resultant granules are then dried in afluid bed dryer until LOD is less than %5 and milled with hammer forwardat 2000-3000 rpm using screen #0050. The milled granulation is thenplaced in a V-Blender with sodium lauryl sulfate and blended for 10minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate,NF, commercially available from Penwest Pharmaceuticals Co. is added,and the mixture is blended for another 5 minutes. The resultantgranulation is then compressed into tablets using a capsule shapedpunch. This final mixture is tableted to approximately 750 mg. Theingredients of the tablets of Examples 26 and 27 are set forth in Table33 below:

TABLE 33 Ex. 26 Ex. 26 Ex. 27 Ex. 27 Component % mg/tab % mg/tab 1Sustained Release Excipient 53.3 400.0 53.3 400.0 2 Diltiazem HCI 32.0240.0 32.0 240.0 3 Fumaric Acid 8.0 60.0 8.0 60.0 4 Surfactant (SLS) 5.340.0 5.3 40.0 5 Sodium Stearyl Fumarate 1.3 0.0 30.0 0.0 6 *Water 27.00.0 30.0 0.0 *Removed during processing

The final tablets in Example 26 have a tablet weight of 750.0 mg. and ahardness of 15 Kp.

The final tablets in Example 27 have a tablet weight of 750.0 mg. and ahardness of 15 Kp.

Dissolution tests were then carried out on the tablets of Example 26 and27 in 250 ML buffer (pH 6) in an automated USP dissolution apparatus(Paddle type DI, 15CPM), and the amount of drug released was analyzedvia UV analysis. The in-vitro are set forth in FIG. 13 and Table 34below:

TABLE 34 Time (hours) Example 25(% dissolved) Example 26 (% dissolved)0.0 0.0 0.0 1.0 18.4 12.6 3.0 32.6 23.9 8.0 59.8 45.9 12.0 80.5 60.316.0 92.3 71.8 24.0 93.7 91.4

Conclusion

Example 26 had a dissolution profile that was slower than Example 25.

Outcome

Dissolution rate can be modified by using different grades of excipient.

Examples 28-29 Effect of Gum:Drug Ratio in Formulation

In Example 28-29, sustained release excipients in accordance with thepresent invention are first prepared, the medicament (in this caseoxybutynin) and the pH modifying agent (in this case being succinicacid) being added subsequently, and the final mixture then beingtableted.

The sustained release excipient is prepared by dispensing xanthan gum,locust bean gum dextrose and calcium sulfate into a high shearmixer/granulator, dispensing ethyl cellulose into a vessel containingethanol, dispensing the ethyl cellulose/ethanol mixture into the xanthangum, locust bean gum, dextrose, calcium sulfate mixture and granulatingto form proper granules, drying the mixture in a fluid bed dryer andmilling the dried material to form proper granules. The ingredients ofthe sustained-release excipient of Examples 28-29 are set forth in Table35 below:

TABLE 35 PREPARATION OF SUSTAINED-RELEASE EXCIPIENT Component Amount(%) - Ex. 28 Amount (%) - Ex. 29 1. Xanthan Gum 20 15 2. Locust Bean Gum30 15 3. Dextrose 40 60 4. Calcium Sulfate 10 10 5. Water* 20-30 20-30*Removed during processing.

Next, the desired amount of oxybutynin and sodium stearyl fumarate arescreened through a 25 mesh sieve, the screened oxybutynin and sustainedrelease excipient are dispensed into a V-blender and blended for 10minutes, the screened sodium stearyl fumarate is added into the blendedmixture of oxybutynin and sustained-release excipient and blended for anadditional 5 minutes, the final blended end product is then compressedinto tablets using a 5/16″ round shaped tooling. This final mixture istableted to approximately 179.4 mg. The ingredients of the tablets ofExamples 28-29 are set forth in Tables 36 and 37 below:

TABLE 36 TABLET FORMULATION - EXAMPLE 28 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Oxybutynin HCL 5.610.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4 Hardness(Kp) 5

TABLE 37 TABLET FORMULATION - EXAMPLE 29 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Oxybutynin HCL 5.610.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4 Hardness(Kp) 5

The final tablets have a tablet weight of 179.4.0 mg and a hardness of 5Kp.

Dissolution tests were then carried out on the tablets of Examples28-29. The in-vitro dissolution results are set forth in Table 38 below.

TABLE 38 Time (hr) Ex. 28 (% dissolved) Ex. 29 (% dissolved) 0.0 0.0 0.02.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5 12.0 108.7 88.920.0 108.7 92.8

The formulation of Example 28 has a drug:gum ratio of 1:5 and theformulation of Example 29 has a drug:gum ratio of 1:8.3. From theresults provided in Table 38, it is evident that the rate of release ofoxybutynin is slower as the drug:gum ratio in the formulations isincreased.

Examples 30-31 Effect of Gum:Dextrose Ratio

In Examples 30-31, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 30 and 31 areset forth in Table 39 below:

TABLE 39 Component Amount(%) Ex. 30 Amount(%) Ex. 31 1 Xanthan Gum 20 152 Locust Bean Gum 30 15 3 Dextrose 40 60 4 Calcium Sulfate 10 10 5Water* 20-30 20-30 *Removed during processing

Thereafter, oxybutynin tablets are prepared as follows:

The desired amount of oxybutynin and sodium stearyl fumarate arescreened through a 25 mesh sieve, the screened oxybutynin and sustainedrelease excipient are dispensed into a V-blender and blended for 10minutes, the screened sodium stearyl fumarate is added into the blendedmixture of oxybutynin and sustained-release excipient and blended for anadditional 5 minutes, the final blended end product is then compressedinto tablets using a 5/16″ round shaped tooling. This final mixture istableted to approximately 179.4 mg. The ingredients of the tablets ofExamples 30-31 are set forth in Tables 40 and 41 below:

TABLE 40 TABLET FORMULATION - EXAMPLE 30 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Oxybutynin HCL 5.610.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4 Hardness(Kp) 5

TABLE 41 TABLET FORMULATION - EXAMPLE 31 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Oxybutynin HCL 5.610.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet weight 179.4 Hardness(Kp) 5

The final tablets have a tablet weight of 17940 mg and a hardness of 5Kp.

Dissolution tests were then carried out on the tablets of Examples30-31. The in-vitro dissolution results are set forth in Table 38 below.

TABLE 42 Time (hr) Ex. 30 (% dissolved) Ex. 31 (% dissolved) 0.0 0.0 0.02.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5 12.0 108.7 88.920.0 108.7 92.8

From the results provided in Table 42, it is evident that as the amountof gum relative to the amount of dextrose is increased, a correspondingdecrease in release of oxybutynin is observed.

Examples 32-35 Effect of Succinic Acid

In Examples 32-33, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 32 and 33 areset forth in Table 43 below:

TABLE 43 Component Amount (%) - Ex. 32-33 1 Xanthan Gum 25 2 Locust BeanGum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl Cellulose 5 6 Water*20-30 *Removed during processing

Thereafter, oxybutynin tablets are prepared as follows:

The desired amount of succinic acid, oxybutynin and sodium stearylfumarate are screened through a 25 mesh sieve, the screened succinicacid and sustained release excipient are dispensed into a V-blender andblended for 10 minutes, the screened oxybutynin is added into theblended mixture of succinic acid and sustained-release excipient andblended for an additional 5 minutes, the screened sodium stearylfumarate is added to the blended mixture of oxybutynin, succinic acidand sustained-release excipient and blended for an additional 5 minutes,the final blended end product is then compressed into tablets using a5/16″ round shaped tooling. The final mixture of Example 32 is tabletedto approximately 251.0 mg and the final mixture of Example 33 istableted to approximately 296.0 mg. The ingredients in Examples 32-33are set forth in Tables 44 and 45 below:

TABLE 44 TABLET FORMULATION - EXAMPLE 32 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 93.2 234.0 2. Succinic Acid N/AN/A 3. Oxybutynin HCL 6 15.0 4. Sodium Stearyl Fumarate 0.8 2.0 Tabletweight 251 Hardness (Kp) 8

The final tablets have a tablet weight of 251.0 mg and a hardness of 8Kp.

TABLE 45 TABLET FORMULATION - EXAMPLE 33 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 92.9 166.7 2. Succinic Acid 15.245.0 2. Oxybutynin HCL 5.1 15.0 3. Sodium Stearyl Fumarate 0.7 2.0Tablet weight 296.0 Hardness (Kp) 8

The final tablets have a tablet weight of 296.0 mg and a hardness of 8Kp.

Dissolution tests were then carried out on the tablets of Examples32-33. The in-vitro dissolution results are set forth in Table 46 below:

TABLE 46 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr) (0%) (15%)0.0 0.0 0.0 2.0 1.3 8.9 4.0 2.1 12.9 6.0 4.7 24.0 8.0 11.3 34.0 12.025.9 44.0 20.0 43.9 59.5

From the results provided in Table 46, it is evident that the additionof Succinic Acid aids in the solubility of the drug substance,therefore, increasing the release rate.

In Examples 34-35, a sustained release excipient is prepared inaccordance with the procedure set forth in Examples 28 and 29. Theingredients of the sustained release excipient of Examples 34 and 35 areset forth in Table 47 below:

TABLE 47 Component Amount (%) - Ex. 34-35 1 Xanthan Gum 25 2 Locust BeanGum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl Cellulose 5 6 Water*20-30 *Removed during processing

Thereafter, oxybutynin tablets are prepared as follows:

The desired amount of sustained-release excipient, succinic acid, andoxybutynin are dispensed into a granulator. They are dry mixed for 3minutes with the impeller at low speed with the chopper blade in the offposition. Water is added over a 1 minute interval, then the mixture isgranulated at high speed for 3 minutes (additional water and granulationtime may be used to form proper granules). Next, the mixture is dried ina fluid bed dryer until the LOD is less than 5%. The dried granulationis milled with the blade forward at 2000-3000 rpm. The milledgranulation and sodium stearyl fumarate are placed into a V-Blender andblended for 10 minutes. The blended mixture is then compressed intotablets using a 5/16″ round shaped tooling. The final mixture of Example34 is tableted to approximately 296.0 mg and the final mixture ofExample 35 is tableted to approximately 266.0 mg. The ingredients inExamples 34-35 are set forth in Tables 48 and 49 below:

TABLE 48 TABLET FORMULATION - EXAMPLE 34 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 79.1 234.0 2. Succinic Acid 15.245.0 3. Oxybutynin HCL 5.1 15.0 4. Sodium Stearyl Fumarate 0.7 2.0 5.Water* 30-45 N/A Tablet weight 296.0 Hardness (Kp) 8 *Removed duringprocessing

The final tablets have a tablet weight of 296.0.0 mg and a hardness of 8Kp.

TABLE 49 TABLET FORMULATION - EXAMPLE 35 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 88.0 234.0 2. Succinic Acid 5.615.0 3. Oxybutynin HCL 5.6 15.0 4. Sodium Stearyl Fumarate 0.8 2.0 5.Water* 30-45 N/A Tablet weight 266.0 Hardness (Kp) 8 *Removed duringprocessing

The final tablets have a tablet weight of 266.0 mg and a hardness of 8Kp.

Dissolution tests were then carried out on the tablets of Examples34-35. The in-vitro dissolution results are set forth in Table 50 below:

TABLE 50 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr) (15%) (6%)0.0 0.0 0.0 2.0 9.2 5.8 4.0 13.7 7.9 6.0 21.2 11.7 8.0 34.2 23.4 12.049.1 37.4 18.0 63.9 57.5

From the results provided in Table 50, it is evident that the higher theamount of Succinic Acid in the formulation the faster the release rate.

Example 36 Effect of Coating Tablets with Ethylcellulose(Surelease®)/Opadry® (80/20) Aqueous Dispersion

The procedure for preparing the Ethylcellulose/Opadry® coating is asfollows:

First, weigh 340 g of Water in a suitable container, add 60 g of Opadry®to the water while mixing. Continue to mix. While mixing the Opadry®dispersion, add 933 g of Ethylcellulose dispersion (Surelease®) andallow to stir for 30-60 minutes. The final dispersion is used to coatthe tablets for a weight gain of 3-5% based on the whole weight of thetablet.

In Example 36, a sustained release excipient is prepared in accordancewith the procedure set forth in Examples 28 and 29. The ingredients ofthe sustained release excipient of Example 36 is set forth in Table 51below:

TABLE 51 Component Amount (%) - Ex. 36 1. Xanthan Gum 25 2. Locust BeanGum 25 3. Dextrose 35 4. Calcium Sulfate 10 5. Ethyl Cellulose 5 6.Water* 20-30 *Removed during processing

Thereafter, oxybutynin tablets are prepared as follows:

The desired amount of sustained-release excipient, succinic acid, andoxybutynin are dispensed into a granulator. They are dry mixed for 3minutes with the impeller at low speed with the chopper blade in the offposition. Water is added over a 1 minute interval, then the mixture isgranulated at high speed for 3 minutes (additional water and granulationtime way be used to form proper granules). Next, the mixture is dried ina fluid bed dryer until, the LOD is less than 5%. The dried granulationis milled with the blade forward at 2000-3000 rpm. The milledgranulation and sodium stearyl fumarate are placed into a V-Blender andblended for 10 minutes. The blended mixture is then compressed intotablets using a 5/16″ round shaped tooling. The final mixture of Example36 is tableted to approximately 296.0 mg. The ingredients in Examples 36is set forth in Table 52 below:

TABLE 52 TABLET FORMULATION - EXAMPLE 36 Component Amount (%) Amount(mg/tab) 1. Sustained Release Excipient 79.1 234.0 2. Succinic Acid 15.245.0 3. Oxybutynin HCL 5.1 15.0 4. Sodium Stearyl Fumarate 0.7 2.0 5.Water* 30-45 N/A Tablet weight 296.0 Hardness (Kp) 8 *Removed duringprocessing

The final tablets have a tablet weight of 296.0.0 mg and a hardness of 8Kp.

Dissolution tests were then carried out on the tablets of Example 36.The in-vitro dissolution results are set forth in Table 53 below:

TABLE 53 Time (hr) Ex. 1 Ex. 2 Ex. 3 0.0 0.0 0.0 0.0 2.0 26.8 7.1 1.74.0 32.1 10.3 2.8 6.0 35.8 14.9 5.5 8.0 40.1 20.2 9.0 12.0 54.2 27.415.1 20.0 72.2 53.2 32.7

From the results provided in Table 53, it is evident that as the amount,by weight of coating increased, the release rate decreased.

Example 37 Effect of Fumaric Acid

In Example 37, a sustained-release excipient is prepared in accordancewith the procedure set forth in Examples 28-29. The ingredients of thesustained-release excipient of Example 37 is set forth in Table 54below:

TABLE 54 Component Amount (%) - Ex. 37 1 Xanthan Gum 25 2 Locust BeanGum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl Cellulose 5 6 Water*20-30 *Removed during processing

TABLET FORMULATION - EXAMPLE 37 Component Amount (mg/tab) 1. SustainedRelease Excipient 166.7 2. Oxybutynin HCL 15 3. Fumaric Acid 30 4.Pruv ® 2 Total (core only) 213.7

The final tablets have a tablet weight of 213.7 mg.

Dissolution tests were then carried out on the tablets of Example 37 incomparison to Ditropan XL. The in-vitro dissolution results are setforth in Table 55 below:

TABLE 55 % Dissolved/Released Time (hr) Ditropan XL 149-141 0 0 0 1 1.95.9 2 3.5 8.5 4 13.4 15.7 8 36.1 43.50 12 60.7 72.1 18 85.0 86.9Recovery 98.4 98.0

Other formulations of Oxybutynin wherein the pH modifying agentcomprises fumaric acid are set forth in Table 56 below:

TABLE 56 Component mg/tab (range) or % as noted 1. Sustained ReleaseExcipient 170-234 mg 2. Fumaric Acid 15-60 mg 3. Oxybutynin HCL 5, 10,15 mg 4. Silicon Dioxide 0-2% 5. Sodium Stearyl Fumarate 1-2%

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

1-64. (canceled)
 65. A sustained release oral tablet comprising asustained release matrix comprising: a therapeutically effective amountof a medicament having a solubility of more than about 10 g/l; a pHmodifying agent which is an organic acid; a sustained release excipientcomprising a gelling agent and an inert pharmaceutical diluent selectedfrom the group consisting of a monosaccharide, a disaccharide, apolyhydric alcohol, and mixtures thereof; an inert pharmaceuticaldiluent selected from the group consisting of monosaccharide, adisaccharide, a polyhydric alcohol, and mixtures thereof, the sustainedrelease excipient further comprising an optional surfactant selectedfrom the group consisting of monovalent alkyl carboxylates, acyllactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalentalkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates,sulfuric acid esters, alkyl sulfates, ethoxylated alkyl sulfates, esterlinked sulfonates, alpha olefin sulfonates, phosphated ethoxylatedalcohols, monoalkyl quaternary ammonium salts, dialkyl quaternaryammonium compounds, amidoamines, aminimides, N-substituted alkyl amides,N-alkyl betaines, sulfobetaines, and N-alkyl β-aminoproprionates, anester of polyethyleneglycol, an ether of polyethyleneglycol, andmixtures of any of the foregoing, and an optional ionizable gel strengthenhancing agent selected from the group consisting of an alkali metalsulfate, an alkali metal chloride, an alkali metal chloride, an alkalimetal borate, an alkali metal bromide, an alkali metal citrate, analkali metal acetate, an alkali metal lactate, an alkaline earth metalsulfate, an alkaline earth metal chloride, an alkaline earth metalchloride, an alkaline earth metal borate, an alkaline earth metalbromide, an alkaline earth metal citrate, an alkaline earth metalacetate, an alkaline earth metal lactate, and mixtures of any of theforegoing; the ingredients of the sustained release excipient beinggranulated together prior to incorporation of the medicament; themedicament being incorporated into the sustained release matrix togetherwith the sustained release excipient and the pH modifying agent suchthat said tablet provides a sustained release of said medicament afteroral administration to human patients for at least about 12 hours or atleast about 24 hours, and the tablet having a total weight from about300 mg to about 1000 mg, wherein the medicament is not oxybutynin. 66.The sustained release oral tablet of claim 65 which provides a sustainedrelease of said medicament for at least about 12 hours after oraladministration.
 67. The sustained release oral tablet of claim 65 whichprovides a sustained release of said medicament for at least about 24hours after oral administration.
 68. The sustained release oral tabletof claim 65, wherein said medicament has a solubility of more than about100 g/l.
 69. The sustained release oral tablet of claim 65, wherein saidmedicament has a solubility of more than about 1000 g/l.
 70. Thesustained release oral tablet of claim 65, wherein the ratio of saidmedicament to said gelling agent is from about 1:5 to about 5:1.
 71. Thesustained release oral tablet of claim 65, wherein the ratio of saidinert diluent to said gelling agent is from about 1:3 to about 3:1 72.The sustained release oral tablet of claim 65, further comprising anionizable gel strength enhancing agent capable of crosslinking with saidgelling agent and increasing the gel strength when the dosage form isexposed to an environmental fluid, the ionizable gel strength enhancingagent comprising an alkali metal or an alkaline earth metal sulfate,chloride, borate, bromide, citrate, acetate, or lactate.
 73. Thesustained release oral tablet of claim 72, wherein said ionizable gelstrength enhancing comprises calcium sulfate.
 74. The sustained releaseoral tablet of claim 65, wherein the gel comprises xanthan gum andlocust bean gum.
 75. The sustained release oral solid tablet of claim65, wherein said organic acid is selected from the group consisting ofcitric acid, succinic acid, fumaric acid, malic acid, maleic acid,glutaric acid, lactic acid and combinations thereof.
 76. The sustainedrelease oral tablet of claim 65, wherein said organic acid is fumaricacid or succinic acid.
 77. The sustained release oral tablet of claim65, wherein said pH modifying agent is present in an amount from about1% to about 10%.
 78. The sustained release oral tablet of claim 65,further comprising a surfactant.
 79. The sustained release oral tabletof claim 78, wherein said surfactant is selected from the groupconsisting of sodium lauryl sulfate and a pharmaceutically effectivesalt of docusate.
 80. The sustained release oral tablet of claim 65,further comprising a hydrophobic or enteric coating on the tablet.
 81. Asustained release oral tablet comprising a sustained release matrixcomprising: a therapeutically effective amount of a medicament having asolubility of more than about 10 g/l; a pH modifying agent which is anorganic acid; a sustained release excipient comprising a gelling agentand an inert pharmaceutical diluent selected from the group consistingof a monosaccharide, a disaccharide, a polyhydric alcohol, and mixturesthereof, an inert pharmaceutical diluent selected from the groupconsisting of monosaccharide, a disaccharide, a polyhydric alcohol, andmixtures thereof, the sustained release excipient further comprising anoptional surfactant selected from the group consisting of anionicsurfactants, cationic surfactants, amphoteric (amphipathic/amphophilic)surfactants, and non-ionic surfactants and an optional ionizable gelstrength enhancing agent which comprises an alkali metal or an alkalineearth metal sulfate, chloride, borate, bromide, citrate, acetate, orlactate; the ingredients of the sustained release excipient beinggranulated together prior to incorporation of the medicament; themedicament being incorporated into the sustained release matrix togetherwith the sustained release excipient and the pH modifying agent suchthat said tablet provides a sustained release of said medicament afteroral administration to human patients for at least about 12 hours or atleast about 24 hours, and the tablet having a total weight from about300 mg to about 1000 mg, wherein the medicament is not oxybutynin. 82.The sustained release oral tablet of claim 81, wherein the ratio of saidinert diluent to said gelling agent is from about 1:3 to about 3:1, andthe pH modifying agent is present in an amount from about 1% to about10%.
 83. The sustained release oral solid tablet of claim 82, whereinsaid organic acid is selected from the group consisting of citric acid,succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid,lactic acid and combinations thereof.
 84. The sustained release oraltablet of claim 83, wherein said organic acid is fumaric acid.
 85. Asustained release oral tablet comprising a sustained release matrixcomprising: a therapeutically effective amount of a medicament having asolubility of more than about 10 g/l; a pH modifying agent which is anorganic acid; a sustained release excipient comprising a gelling agentand an inert pharmaceutical diluent selected from the group consistingof a monosaccharide, a disaccharide, a polyhydric alcohol, and mixturesthereof, an inert pharmaceutical diluent selected from the groupconsisting of monosaccharide, a disaccharide, a polyhydric alcohol, andmixtures thereof, the sustained release excipient further comprising anoptional surfactant and an optional ionizable gel strength enhancingagent which are not an organic acid; the ingredients of the sustainedrelease excipient being granulated together prior to incorporation ofthe medicament; the medicament being incorporated into the sustainedrelease matrix together with the sustained release excipient and the pHmodifying agent such that said tablet provides a sustained release ofsaid medicament after oral administration to human patients for at leastabout 12 hours or at least about 24 hours, and the tablet having a totalweight from about 300 mg to about 1000 mg, wherein the medicament is notoxybutynin.
 86. The sustained release oral tablet of claim 85, whereinthe ratio of said inert diluent to said gelling agent is from about 1:3to about 3:1, and the pH modifying agent is present in an amount fromabout 1% to about 10%.
 87. The sustained release oral solid tablet ofclaim 86, wherein said organic acid is selected from the groupconsisting of citric acid, succinic acid, fumaric acid, malic acid,maleic acid, glutaric acid, lactic acid and combinations thereof.